Archive for the ‘Pain: Etiology, Genetics & Innovations in Treatment’ Category

Opioids, Pain, And Palliative Care [6.3.9]

Curator: Stephen J. Williams, Ph.D.

As written by Hrachya Nersesyan and Konstantin V Slavin in Current approach to cancer pain management: Availability and implications of different treatment options in Ther Clin Risk Manag. 2007 Jun; 3(3): 381–400

According to statistics published by the American Cancer Society in 2002, “50%–70% of people with cancer experience some degree of pain” (ACS 2002), which usually only intensifies as the disease progresses. Less than half get adequate relief of their pain, which negatively impacts their quality of life. The incidence of pain in advanced stages of invasive cancer approaches 80% and it is 90% in patients with metastases to osseous structures (Pharo and Zhou 2005).

Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain). However, there has been difficulty in modeling cancer-induced pain in animals. This has hampered our understanding and therapeutic intervention of the clinical situation, especially concerning ovarian cancer patients.   It has been shown that 85% of ovarian cancer patients in palliative care (during last two months of life) still report severe pain although 54% of these women were given high intensity pain medications such as morphine, still the mainstream pain medication for severe cancer-associated pain. Admittedly, more research into the ability of cancer to provoke pain and sensitize the central nervous system, is warranted, as well as development of new methods of analgesia for cancer-associated pain at end-of-life. Therefore, in collaboration with several colleagues, in vivo models of nociceptive and neuropathic pain will be integrated with my co-developed in vivo tumor models of ovarian cancer. This tumor model allows for noninvasive monitoring of tumor burden without the need for anesthesia, as necessitated by imaging strategies to quantitate tumor burden, such as bioluminescence and MRI.

Even in an era of promising new cancer therapies, cancer pain is one of the highest concerns for the patient, their clinician, and surrounding loved ones, especially impacting quality of life during palliative care. Over half of cancer patients have reported severe pain in the course of their disease (List MA J Clin Oncol 2000 18:877-84) and the statistics are worse for ovarian cancer patients, regardless whether during treatment or in palliative care (see below review).

Journal of Pain and Symptom Management Volume 33, Issue 1 , Pages 24-31, January 2007

Pain Management in the Last Six Months of Life Among Women Who Died of Ovarian Cancer

Sharon J. Rolnick, PhD, MPH, Jody Jackson, RN, BSN, Winnie W. Nelson, PharmD, MS, Amy Butani, BA, Lisa J. Herrinton, PhD, Mark Hornbrook, PhD, Christine Neslund-Dudas, MA, Don J. Bachman, MS, Steven S. Coughlin, PhD

HealthPartners Research Foundation (S.J.R., J.J., A.B.), Minneapolis, Minnesota; Applied Health Outcomes (W.W.N.), Palm Harbor, Florida; Division of Research (L.J.H., D.J.B.), Kaiser Permanente Northern California, Oakland, California; Kaiser Permanente Center for Health Research (M.H.), Portland, Oregon; Josephine Ford Cancer Center (C.N.-D.), Henry Ford Health System, Detroit, Michigan; and National Center for Chronic Disease Prevention and Health Promotion (S.S.C.), Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract Previous studies indicate that the symptoms of many dying cancer patients are undertreated and many suffer unnecessary pain. We obtained data retrospectively from three large health maintenance organizations, and examined the analgesic drug therapies received in the last six months of life by women who died of ovarian cancer between 1995 and 2000. Subjects were identified through cancer registries and administrative data. Outpatient medications used during the final six months of life were obtained from pharmacy databases. Pain information was obtained from medical charts. We categorized each medication based on the World Health Organization classification for pain management (mild, moderate, or intense). Of the 421 women, only 64 (15%) had no mention of pain in their charts. The use of medications typically prescribed for moderate to severe pain (“high intensity” drugs) increased as women approached death. At 5–6 months before death, 55% of women were either on no pain medication or medication generally used for mild pain; only 9% were using the highest intensity regimen. The percentage on the highest intensity regimen (drugs generally used for severe pain) increased to 22% at 3–4 months before death and 54% at 1–2 months. Older women (70 or older) were less likely to be prescribed the highest intensity medication than those under age 70 (44% vs. 70%, P<0.001). No differences were found in the use of the high intensity drugs by race, marital status, year of diagnosis, stage of disease, or comorbidity. Our finding that only 54% of women with pain were given high intensity medication near death indicates room for improvement in the care of ovarian cancer patients at the end of life.

Cancer pain is a complexity concerning not only the peripheral and central nervous systems but the cancer cell, the tumor microenvironment, and tumor infiltrating immune cells and inflammatory mediators. The goal of this article is to briefly introduce these factors governing pain in the cancer patient and a discussion of animal models of pain in relation to cancer.

Pain is considered as either termed nociceptive pain (activations and sensitization of primary afferent “nociceptor” neurons or neuropathic pain (damage to sensory nerves). Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain).

For a great review please see Dr. Kara’s curation The Genetics of Pain: An Integrated Approach.

Palliative Care

For a good review please see the following LINK on Palliative Care

Palliative Care_4.6

Please See VIDEOs on Cancer, Pain and Palliative Care





From ACS Guideline: Developing a plan for pain control

The first step in developing a pain control plan is talking with your cancer care team about your pain. You need to be able to describe your pain to your family or friends, too. You may want to have your family or friends help you talk to your cancer care team about your pain, especially if you’re too tired or in too much pain to talk to them yourself.

Using a pain scale is a helpful way to describe how much pain you’re feeling. To use the Pain Intensity Scale shown here, try to assign a number from 0 to 10 to your pain level. If you have no pain, use a 0. As the numbers get higher, they stand for pain that’s getting worse. A 10 means the worst pain you can imagine.

0 1 2 3 4 5 6 7 8 9 10
No pain Worst pain

For instance, you could say, “Right now, my pain is a 7 on a scale of 0 to 10.”

You can use the rating scale to describe:

  • How bad your pain is at its worst
  • What your pain is like most of the time
  • How bad your pain is at its least
  • How your pain changes with treatment

Tell your cancer care team and your family or friends:

  • Where you feel pain
  • What it feels like – for instance, sharp, dull, throbbing, gnawing, burning, shooting, steady
  • How strong the pain is (using the 0 to 10 scale)
  • How long it lasts
  • What eases the pain
  • What makes the pain worse
  • How the pain affects your daily life
  • What medicines you’re taking for the pain and how much relief you get from them

NCCN Adult Cancer-Associated Pain Guidelines (see PDF)NCCN adult pain guidelines

NCCN gives a comprehensive guideline to Cancer Patient Pain Management for Caregivers, physicians, and educational materials for patients.

The attached PDF gives information on

  • Pain Definition and Pain Management Principles
  • Pain Screening, Rating and Assessment Guidelines
  • Management of Patients with Differing Opioid Tolerance
  • Opioid Titration Guidelines
  • Adjuvant Analgesia
  • Psychosocial Support

Table. Important Points in NCCN Guidelines for Pain Management

Pain Severity (pain scale level) guideline
All pain levels – Opioid maintenance, – psychosocial support, – caregiver education
Severe Pain (7-10) – Reevaluate opioid titration
Moderate (4-6) – Continue opioid titration

– Consider specific pain syndrome problem and consultation

– continue analgesic titration

Mild (0-3) Adjuvant analgesics

The clinical presentation of cancer pain depends on the histologic type of cancer, the location of the primary neoplasm, and location of metastases. (for example pain in breast cancer patients have different pain issues than patients with oral.cancer).

However, high grade serous ovarian cancer, the most clinically prevalent of this disease, usually presents as an ascitic carcinomatosis, spread throughout the peritoneum and mesothelium.

Ovarian cancer stem cells and mediators of pain

Although not totally accepted by the field, a discussion of ovarian cancer stem cells is warranted, especially in light of this discussion. Cancer stem cells are considered that subpopulation of cells in the bulk tumor exhibiting self-renewing capacity, generally resistant to chemotherapy, and therefore repopulate the tumor with new tumor cells. In this case, ovarian cancer stem cells could be more pertinent to the manifestations of pain than bulk tumor, as these cells would survive chemotherapy. This may be the case, as ovarian cancer pain may not be associated with overall tumor burden? Are there PAIN MEDIATORS secreted from ovarian cancer cells?

Some Known Pain Mediators Secreted from Ovarian Tumor Cells


Proteases and Protease-Activated Receptors

Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, Pasricha PJ

J Neurosci. 2001 Nov 15; 21(22):9036-42.

Alier KA, Endicott JA, Stemkowski PL, Cenac N, Cellars L, Chapman K, Andrade-Gordon P, Vergnolle N, Smith PA.J Pharmacol Exp Ther. 2008 Jan; 324(1):224-33.


Sevcik MA, Ghilardi JR, Halvorson KG, Lindsay TH, Kubota K, Mantyh PW

J Pain. 2005 Nov; 6(11):771-5

Nerve Growth Factor

Tumor Necrosis Factor

Opioids: A Reference

Opioid analgesics: analgesia without loss of consciousness

Three main uses of opioids

  1. Analgesia
  2. Antitussive
  3. Diarrhea

1954 – nalorphine, partial antagonists had analgesic effect. Morphine: Morpheus – Greek God of dreams

1) opiates: opium alkaloids including morphine, codeine, thebaine, papavarine

2) synthetic: meperedine, methadone


  • Antagonist properties associated with replacement of the methyl substituent on nitrogen atom with large group (naloxone and nalorphine replaced with allyl group)
  • Pharmacokinetic properties affected by C3 and C6 hydroxyl substitutions
  • CH3 at phenolic OH at C3 reduces first pass metabolism by glucoronidation THEREFORE codeine and oxycodeine have higher oral availability
  • Acetylation of both OH groups on morphine : heroin penetrates BBB : rapidly hydrolyzed to give monoacetylmorphine and morphine


  • Well absorbed from s.c., i.m., oral
  • Codeine and hydrocodeine higher absorption from oral:parental ratio because of extensive first pass metabolism
  • Most opioids are well absorbed orally but DECREASE potency due to first pass
  • Variable plasma protein binding
  • Brain distribution is actually low but opioids are very potent
  • Well distributed and may accumulate in skeletal muscle
  • Fentynyl (lipophilic) may accumulate in fat



  • Most opioids converted to polar metabolites so excreted by kidney ;IMPORTANT prolonged analgesia in patients with renal disease
  • Esters like meperidine and herion metabolized by tissue esterases
  • Glucoronidated morphine may have analgesic properties



All three (mu, kappa, and delta) activate pertussis toxin sensitive G protein {Gi}

Opioids quiet pain (nociceptive) neurons by inhibiting nerve conduction (decrease entry of calcium or increase entry of potassium)

There are four major subtypes of opioid receptors:[12]

Receptor Subtypes Location[13][14] Function[13][14]
delta (δ)
OP1 (I)
δ1,[15] δ2
kappa (κ)
OP2 (I)
κ1, κ2, κ3
mu (μ)
OP3 (I)
μ1, μ2, μ3 μ1:



  • possible vasodilation
Nociceptin receptor
  • anxiety
  • depression
  • appetite
  • development of tolerance to μ-opioid agonists

Tolerance and Physical Dependence

Tolerance: gradual loss of effectiveness over repeated doses

Physical Dependence: when tolerance develops continued administration of drug required to prevent physical withdrawal symptoms

  • With opioids see tolerance most with the analgesic, sedative, and antitussive effects; not so much with antidiarrheal effects

Major effects of opioids on Organ Systems

  • CNS
    1. Analgesia – raise threshhold for pain
    2. Euphoria – pleasant floating feeling but sometimes dysphoria (agitation)
    3. Sedation –drowsiness but no amnesia; more frequent in elderly than young but can disrupt normal REM sleep
    4. Respiratory depression – ALL opioids produce significant resp. depression by inhibiting the brain stem; careful in patients with impaired respiratory function like COPD or increased intracranial pressure
    5. Cough suppression – tolerance can develop; may increase airway secretions
    6. Miosis – constriction of pupils; seen with ALL agonists; treat with atropine
    7. Rigidity – mostly seen with fentanyl; treat with opioid antagonist like nalozone
    8. Emesis; naseua, vomiting


  • Peripheral
    1. Cardiovascular – no real major effects; some specific compounds may have effects on blood pressure
    2. GI – Constipation most common; loperamide (Immodium); pentazocine may cause less constipation; problem for treating cancer patients for pain; opioid receptors do exist in the GI tract but effect may be CNS as well as local
    3. Biliary system – minor, may cause constriction of bile duct
    4. GU (genitourinary) – reduced urine output by increased antidiuretic hormone
    5. Uterus – may prolong labor
    6. Neuroendocrine – opioid analgesics can stimulate release of ADH, prolactin
    7. Other – opioid analgesics may cause flushing and warming of skin; release of histamine?


Specific Agents

Strong Agonists

  1. Phenanthrenes –all are used for analgesia
  • Morphine
  • Hydromorphone
  • Oxymorphone
  • Heroin
  1. Phenylheptylamine
  • Methadone – longer acting than morphine; tolerance and physical dependency slower to develop than with morphine; low doses of methadone may be used for heroin addict undergoing withdrawal
  1. Phenyllpiperidines
  • Meperidine
  • Fentanyl (also sufentanil) which is 5-7 more times potent than fentanyl. Negative inotropic (contractile force) effects on heart
  1. Levorphanol

Mild to Moderate Agonist

  1. Phenanthrenes – most given in combo with NSAID
  • Codeine – antitussive, some analgesia
  • Oxycodone
  • Dihydrocodone
  • Hydrocodone
  1. Propoxyphene – Darvon, low abuse and low analgesia compared to morphine
  2. Phenylpiperidines
  • Diphenoxylate –used for diarrhea; not for analgesia and no abuse potential
  • Loperamide – antidiarrheal (Imodium), low abuse potential

Mixed Agonist-Antagonist & Partial Agonists

  1. Nalbulphine – strong kappa agonist and mu antagonist.. Analgesic
  2. Buprenorphine – analgesic. Partial mu agonist has long duration. Slow dissocation from receptor makes resistant to naloxone reversal
  3. Buterphanol – analgesia with sedation, kappa agonist
  4. Pentazocine – kappa agonist with weak mu antagonism.Is an irritant so do no inject s.c.


  1. Naloxone – quick reversal of opioid agonist action (1-2 hours); not well absorbed orally; pure antagonist so no effects by itself; no tolerance problems; opioid antidote
  2. Naltrexone – well absorbed orally can be used in maintenance therapy because of long duration of action


  1. Codeine
  2. Dextromethorphan
  3. Levoproposyphen
  4. Noscapine

Other posts related to Pain, Cancer, and Palliative Care on this Open Access Journal Include

Palliative Care_4.6

Requiem for Palliative Cardiology: The Voice of Dr. Esselstyn on Plant-Based Nutrition

Cancer and Nutrition

Thyme Oil Beats Ibuprofen for Pain Management.

Pain Management Drug Market: Insight Pharma Reports

New target for chronic pain treatment found

The Genetics of Pain: An Integrated Approach

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NIMHD welcomes nine new members to the National Advisory Council on Minority Health and Health Disparities

Reporter: Stephen J. Williams, Ph.D.

The National Institute on Minority Health and Health Disparities (NIMHD) has announced the appointment of nine new members to the National Advisory Council on Minority Health and Health Disparities (NACMHD), NIMHD’s principal advisory board. Members of the council are drawn from the scientific, medical, and lay communities, so they offer diverse perspectives on minority health and health disparities.

The NACMHD, which meets three times a year on the National Institutes of Health campus, Bethesda, Maryland, advises the secretary of Health and Human Services and the directors of NIH and NIMHD on matters related to NIMHD’s mission. The council also conducts the second level of review of grant applications and cooperative agreements for research and training and recommends approval for projects that show promise of making valuable contributions to human knowledge.

The next meeting of the NACMHD will be held on Thursday, Sept. 10, 8:30 a.m.-5:00 p.m. on the NIH campus. The meeting will be available on videocast at http://www.videocast.nih.gov.

NIMHD Director Eliseo J. Pérez-Stable, M.D., is pleased to welcome the following new members

Margarita Alegría, Ph.D., is the director of the Center for Multicultural Mental Health Research at Cambridge Health Alliance and a professor in the department of psychiatry at Harvard Medical School, Boston. She has devoted her career to researching disparities in mental health and substance abuse services, with the goal of improving access to and equity and quality of these services for disadvantaged and minority populations.

Maria Araneta, Ph.D., a perinatal epidemiologist, is a professor in the Department of Family and Preventive Medicine at the University of California, San Diego. Her research interests include maternal/pediatric HIV/AIDS, birth defects, and ethnic health disparities in type 2 diabetes, regional fat distribution, cardiovascular disease, and metabolic abnormalities.

Judith Bradford, Ph.D., is director of the Center for Population Research in LGBT Health and she co-chairs The Fenway Institute, Boston. Dr. Bradford has participated in health research since 1984, working with public health programs and community-based organizations to conduct studies on lesbian, gay, bisexual, and transgender people and racial minority communities and to translate the results into programs to reduce health disparities.

Linda Burhansstipanov, Dr.P.H., has worked in public health since 1971, primarily with Native American issues. She is a nationally recognized educator on cancer prevention, community-based participatory research, navigation programs, cultural competency, evaluation, and other topics. Dr. Burhansstipanov worked with the Anschutz Medical Center Cancer Research Center — now the University of Colorado Cancer Research Center — in Denver for five years before founding Native American Cancer Initiatives, Inc., and the Native American Cancer Research Corporation.

Sandro Galea, M.D., a physician and epidemiologist, is the dean and a professor at the Boston University School of Public Health. Prior to his appointment at Boston University, Dr. Galea served as the Anna Cheskis Gelman and Murray Charles Gelman Professor and chair of the Department of Epidemiology at the Columbia University Mailman School of Public Health, New York City. His research focuses on the causes of brain disorders, particularly common mood and anxiety disorders, and substance abuse.

Linda Greene, J.D., is Evjue Bascom Professor of Law at the University of Wisconsin–Madison Law School. Her teaching and academic scholarship include constitutional law, civil procedure, legislation, civil rights, and sports law. Most recently, she was the vice chancellor for equity, diversity, and inclusion at the University of California, San Diego.

Ross A. Hammond, Ph.D., a senior fellow in the Economic Studies Program at the Brookings Institution, Washington, D.C., is also director of the Center on Social Dynamics and Policy. His primary area of expertise is using mathematical and computational methods from complex systems science to model complex dynamics in economic, social, and public health systems. His current research topics include obesity etiology and prevention, tobacco control, and behavioral epidemiology.

Hilton Hudson, II, M.D., is chief of cardiothoracic surgery at Franciscan Healthcare, Munster, Indiana and a national ambassador for the American Heart Association. He also is the founder of Hilton Publishing, Inc., a national publisher dedicated to producing content on solutions related to health, wellness, and education for people in underserved communities. Dr. Hilton’s book, “The Heart of the Matter: The African American Guide to Heart Disease, Heart Treatment and Heart Wellness” has impacted at-risk patients nationwide.

Brian M. Rivers, Ph.D., M.P.H., currently serves on the research faculty at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. He is also an assistant professor in the Department of Oncologic Sciences at the University of South Florida College of Medicine, Tampa. Dr. Rivers’ research efforts include examination of unmet educational and psychosocial needs and the development of communication tools, couple-centered interventions, and evidence-based methods to convey complex information to at-risk populations across the cancer continuum.

NIMHD is one of NIH’s 27 Institutes and Centers. It leads scientific research to improve minority health and eliminate health disparities by conducting and supporting research; planning, reviewing, coordinating, and evaluating all minority health and health disparities research at NIH; promoting and supporting the training of a diverse research workforce; translating and disseminating research information; and fostering collaborations and partnerships. For more information about NIMHD, visit http://www.nimhd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

Curator and Interviewer: Stephen J. Williams, Ph.D.


philly2nightThis post is the third in a series of posts highlighting interviews with Philadelphia area biotech startup CEO’s and show how a vibrant biotech startup scene is evolving in the city as well as the Delaware Valley area. Philadelphia has been home to some of the nation’s oldest biotechs including Cephalon, Centocor, hundreds of spinouts from a multitude of universities as well as home of the first cloned animal (a frog), the first transgenic mouse, and Nobel laureates in the field of molecular biology and genetics. Although some recent disheartening news about the fall in rankings of Philadelphia as a biotech hub and recent remarks by CEO’s of former area companies has dominated the news, biotech incubators like the University City Science Center and Bucks County Biotechnology Center as well as a reinvigorated investment community (like PCCI and MABA) are bringing Philadelphia back. And although much work is needed to bring the Philadelphia area back to its former glory days (including political will at the state level) there are many bright spots such as the innovative young companies as outlined in these posts.

In today’s post, I had the opportunity to talk with both Dr. William Kinney, Chief Scientific Officer and Thoma Kikis, Founder/CMO of KannaLife Sciences based in the Pennsylvania Biotech Center of Bucks County.   KannaLifeSciences, although highlighted in national media reports and Headline news (HLN TV)for their work on cannabis-derived compounds, is a phyto-medical company focused on the discipline surrounding pharmacognosy, the branch of pharmacology dealing with natural drugs and their constituents.

Below is the interview with Dr. Kinney and Mr. Kikis of KannaLife Sciences and Leaders in Pharmaceutical Business Intelligence (LPBI)


PA Biotech Questions answered by Dr. William Kinney, Chief Scientific Officer of KannaLife Sciences



LPBI: Your parent company   is based in New York. Why did you choose the Bucks County Pennsylvania Biotechnology Center?


Dr. Kinney: The Bucks County Pennsylvania Biotechnology Center has several aspects that were attractive to us.  They have a rich talent pool of pharmaceutically trained medicinal chemists, an NIH trained CNS pharmacologist,  a scientific focus on liver disease, and a premier natural product collection.


LBPI: The Blumberg Institute and Natural Products Discovery Institute has acquired a massive phytochemical library. How does this resource benefit the present and future plans for KannaLife?


Dr. Kinney: KannaLife is actively mining this collection for new sources of neuroprotective agents and is in the process of characterizing the active components of a specific biologically active plant extract.  Jason Clement of the NPDI has taken a lead on these scientific studies and is on our Advisory Board. 


LPBI: Was the state of Pennsylvania and local industry groups support KannaLife’s move into the Doylestown incubator?


Dr. Kinney: The move was not State influenced by state or industry groups. 


LPBI: Has the partnership with Ben Franklin Partners and the Center provided you with investment opportunities?


Dr. Kinney: Ben Franklin Partners has not yet been consulted as a source of capital.


LPBI: The discipline of pharmacognosy, although over a century old, has relied on individual investigators and mainly academic laboratories to make initial discoveries on medicinal uses of natural products. Although there have been many great successes (taxol, many antibiotics, glycosides, etc.) many big pharmaceutical companies have abandoned this strategy considering it a slow, innefective process. Given the access you have to the chemical library there at Buck County Technology Center, the potential you had identified with cannabanoids in diseases related to oxidative stress, how can KannaLife enhance the efficiency of finding therapeutic and potential preventive uses for natural products?


Dr. Kinney: KannaLife has the opportunity to improve upon natural molecules that have shown medically uses, but have limitations related to safety and bioavailability. By applying industry standard medicinal chemistry optimization and assay methods, progress is being made in improving upon nature.  In addition KannaLife has access to one of the most commercially successful natural products scientists and collections in the industry.


LPBI: How does the clinical & regulatory experience in the Philadelphia area help a company like Kannalife?


Dr. Kinney: Within the region, KannaLife has access to professionals in all areas of drug development either by hiring displaced professionals or partnering with regional contract research organizations.


LPBI  You are focusing on an interesting mechanism of action (oxidative stress) and find your direction appealing (find compounds to reverse this, determine relevant disease states {like HCE} then screen these compounds in those disease models {in hippocampal slices}).  As oxidative stress is related to many diseases are you trying to develop your natural products as preventative strategies, even though those type of clinical trials usually require massive numbers of trial participants or are you looking to partner with a larger company to do this?


Dr. Kinney: Our strategy is to initially pursue Hepatic Encephalophy (HE) as the lead orphan disease indication and then partner with other organizations to broaden into other areas that would benefit from a neuroprotective agent.  It is expected the HE will be responsive to an acute treatment regimen.   We are pursuing both natural products and new chemical entities for this development path.



General Questions answered by Thoma Kikis, Founder/CMO of KannaLife Sciences


LPBI: How did KannaLife get the patent from the National Institutes of Health?


My name is Thoma Kikis I’m the co-founder of KannaLife Sciences. In 2010, my partner Dean Petkanas and I founded KannaLife and we set course applying for the exclusive license of the ‘507 patent held by the US Government Health and Human Services and National Institutes of Health (NIH). We spent close to 2 years working on acquiring an exclusive license from NIH to commercially develop Patent 6,630,507 “Cannabinoids as Antioxidants and Neuroprotectants.” In 2012, we were granted exclusivity from NIH to develop a treatment for a disease called Hepatic Encephalopathy (HE), a brain liver disease that stems from cirrhosis.


Cannabinoids are the chemicals that compose the Cannabis plant. There are over 85 known isolated Cannabinoids in Cannabis. The cannabis plant is a repository for chemicals, there are over 400 chemicals in the entire plant. We are currently working on non-psychoactive cannabinoids, cannabidiol being at the forefront.


As we started our work on HE and saw promising results in the area of neuroprotection we sought out another license from the NIH on the same patent to treat CTE (Chronic Traumatic Encephalopathy), in August of 2014 we were granted the additional license. CTE is a concussion related traumatic brain disease with long term effects mostly suffered by contact sports players including football, hockey, soccer, lacrosse, boxing and active military soldiers.


To date we are the only license holders of the US Government held patent on cannabinoids.



LPBI: How long has this project been going on?


We have been working on the overall project since 2010. We first started work on early research for CTE in early-2013.



LPBI: Tell me about the project. What are the goals?


Our focus has always been on treating diseases that effect the Brain. Currently we are looking for solutions in therapeutic agents designed to reduce oxidative stress, and act as immuno-modulators and neuroprotectants.


KannaLife has an overall commitment to discover and understand new phytochemicals. This diversification of scientific and commercial interests strongly indicates a balanced and thoughtful approach to our goals of providing standardized, safer and more effective medicines in a socially responsible way.


Currently our research has focused on the non-psychoactive cannabidiol (CBD). Exploring the appropriate uses and limitations and improving its safety and Metered Dosing. CBD has a limited therapeutic window and poor bioavailability upon oral dosing, making delivery of a consistent therapeutic dose challenging. We are also developing new CBD-like molecules to overcome these limitations and evaluating new phytochemicals from non-regulated plants.


KannaLife’s research is led by experienced pharmaceutically trained professionals; Our Scientific team out of the Pennsylvania Biotechnology Center is led by Dr. William Kinney and Dr. Douglas Brenneman both with decades of experience in pharmaceutical R&D.



LPBI: How do cannabinoids help neurological damage? -What sort of neurological damage do they help?


Cannabinoids and specifically cannabidiol work to relieve oxidative stress, and act as immuno-modulators and neuroprotectants.


So far our pre-clinical results show that cannabidiol is a good candidate as a neuroprotectant as the patent attests to. Our current studies have been to protect neuronal cells from toxicity. For HE we have been looking specifically at ammonia and ethanol toxicity.



– How did it go from treating general neurological damage to treating CTE? Is there any proof yet that cannabinoids can help prevent CTE? What proof?


We started examining toxicity first with ammonia and ethanol in HE and then posed the question; If CBD is a neuroprotectant against toxicity then we need to examine what it can do for other toxins. We looked at CTE and the toxin that causes it, tau. We just acquired the license in August from the NIH for CTE and are beginning our pre-clinical work in the area of CTE now with Dr. Ron Tuma and Dr. Sara Jane Ward at Temple University in Philadelphia.



LPBI: How long until a treatment could be ready? What’s the timeline?


We will have research findings in the coming year. We plan on filing an IND (Investigational New Drug application) with the FDA for CBD and our molecules in 2015 for HE and file for CTE once our studies are done.



LPBI: What other groups are you working with regarding CTE?


We are getting good support from former NFL players who want solutions to the problem of concussions and CTE. This is a very frightening topic for many players, especially with the controversy and lawsuits surrounding it. I have personally spoken to several former NFL players, some who have CTE and many are frightened at what the future holds.


We enrolled a former player, Marvin Washington. Marvin was an 11 year NFL vet with NY Jets, SF 49ers and won a SuperBowl on the 1998 Denver Broncos. He has been leading the charge on KannaLife’s behalf to raise awareness to the potential solution for CTE.


We tried approaching the NFL in 2013 but they didn’t want to meet. I can understand that they don’t want to take a position. But ultimately, they’re going to have to make a decision and look into different research to treat concussions. They have already given the NIH $30 Million for research into football related injuries and we hold a license with the NIH, so we wanted to have a discussion. But currently cannabinoids are part of their substance abuse policy connected to marijuana. Our message to the NFL is that they need to lead the science, not follow it.


Can you imagine the NFL’s stance on marijuana treating concussions and CTE? These are topics they don’t want to touch but will have to at some point.


LPBI: Thank you both Dr. Kinney and Mr. Kikis.


Please look for future posts in this series on the Philly Biotech Scene on this site

Also, if you would like your Philadelphia biotech startup to be highlighted in this series please contact me or

http://pharmaceuticalintelligence.com at:

sjwilliamspa@comcast.net or @StephenJWillia2  or @pharma_BI.

Our site is read by ~ thousand international readers DAILY and thousands of Twitter followers including venture capital.


Other posts on this site in this VIBRANT PHILLY BIOTECH SCENE SERIES OR referring to PHILADELPHIA BIOTECH include:

The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia

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Neural Activity Regulating Endocrine Response

Writer and Curator: Larry H. Bernstein, MD, FCAP


Defensive responses of Brandt’s voles (Lasiopodomys brandtii) to chronic predatory stress

Ibrahim M. Hegab, Guoshen Shang, Manhong Ye, Yajuan, et al.
Physiology & Behavior 126 (2014) 1–7

Predator odors are non-intrusive natural stressors of high ethological relevance. The objective of this study was to investigate the processing of a chronic, life-threatening stimulus during repeated prolonged presentation to Brandt’s voles. One hundred and twenty voles were tested by repeated presentation of cat feces in a defensive withdrawal apparatus. Voles exposed to feces for short periods showed more avoidance, more concealment in the hide box, less contact time with the odor source, more freezing behavior, less grooming, more jumping, and more vigilant rearing than did non-exposed voles, and those exposed for longer periods. Serum levels of adrenocortico-tropic hormone and corticosterone increased significantly when animals were repeatedly exposed to cat feces for short periods. The behavioral and endocrine responses  habituated during prolonged presentation of cat feces.  ΔfosB mRNA expression level was highest in voles exposed to cat feces for 6 and 12 consecutive days, and subsequently declined in animals exposed to cat feces for 24 days. We therefore conclude that the behavioral and endocrine responses to repeated exposure to cat feces undergo a process of habituation, while ΔfosB changes in the medial hypothalamic region exhibit sensitization. We propose that habituation and sensitization are complementary rather than contradictory processes that occur in the same individual upon repeated presentation of the same stressor.

Neuroendocrine changes upon exposure to predator odors

Ibrahim M. Hegab, Wanhong Wei
Physiology & Behavior 131 (2014) 149–155

Predator odors are non-intrusive and naturalistic stressors of high ethological relevance in animals. Upon exposure to a predator or its associated cues, robust physiological and molecular anti-predator defensive strategies are

elicited thereby allowing prey species to recognize, avoid and defend against a possible predation threat. In this review, we will discuss the nature of neuroendocrine stress responses upon exposure to predator odors. Predator odors can have a profound effect on the endocrine system, including activation of the hypothalamic–pituitary–adrenal axis, and induction of stress hormones such as corticosterone and adrenocorticotropic hormone. On a neural level, short-term exposure to predator odors leads to induction of the c-fos gene, while induction of ΔFosB in a different brain region is detected under chronic predation stress. Future research should aim to elucidate the relationships between neuroendocrine and behavioral outputs to gage the different levels of antipredator responses in prey species.

Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring

Hongli Sun, Ning Jia, Lixia Guan, Qing Su, et al.
Behavioural Brain Research 257 (2013) 1– 7

Prenatal stress (PS) has been shown to be associated with anxiety. However, the underlying neurological mechanisms are not well understood. To determine the effects of PS on anxiety-like behavior in the adult offspring, we evaluated anxiety-like behavior using open field test (OFT) and elevated plus maze (EPM) in the 3-month offspring. Both male and female offspring showed a significant reduction of crossing counts in the center, total crossing counts, rearing counts and time spent in the center in the OFT, and only male offspring showed a decreased percentage of open-arm entries and open-arm time in open arms in the EPM. Additionally, expression of NR1 and NR2A subunit of N-methyl-d-aspartate receptor (NMDAR) in the hippocampus (HIP), prefrontal cortex (PFC) and striatum (STR) was studied. Our results showed that PS reduced NR1 and NR2A expression in the HIP, NR2A expression in the PFC and STR in the offspring. The altered NR1 and NR2A could have potential impact on anxiety-like behavior in the adult offspring exposed to PS.

Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation

Dietmar Hestermann, Yasin Temel, Arjan Bloklan, Lee Wei Lim

Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior – has robust 5-HT fibers and reciprocal connections with the hypothalamic–pituitary–adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment
and the PAG neural correlates of the behavior remain largely unknown. In
this study, the effects of acute and chronic treatments with buspirone (BUSP)
and escitalopram (ESCIT) on anxiety related behaviors were tested in an open-
field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos-ir. No significant differences were found in behaviors and CORT after chronic treatment.
In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and
the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment.

Neuroendocrine mechanisms for immune system regulation during stress in fish

Gino Nardocci,, Cristina Navarro, Paula P. Cortes, Monica Imarai
Fish & Shellfish Immunology 40 (2014) 531e538

In the last years, the aquaculture crops have experienced an explosive and intensive growth, because of the high demand for protein. This growth has increased fish susceptibility to diseases and subsequent death. The constant biotic and abiotic changes experienced by fish species in culture are challenges that induce physiological, endocrine and immunological responses. These changes mitigate stress effects at the cellular level to maintain homeostasis. The effects of stress on the immune system have been studied for many years. While acute stress can have beneficial effects, chronic stress inhibits the immune response in mammals and teleost fish. In response to stress, a signaling cascade is triggered by the activation of neural circuits in the central nervous system because the hypothalamus is the central modulator of stress. This leads to the production of catecholamines, corticosteroid-releasing hormone, adrenocorticotropic hormone and glucocorticoids, which are the essential neuroendocrine mediators for this activation. Because stress situations are energetically demanding, the neuroendocrine signals are involved in metabolic support and will suppress the “less important” immune function.  Understanding the cellular mechanisms of the neuroendocrine regulation of immunity in fish will allow the development of new pharmaceutical strategies and therapeutics for the prevention and treatment of diseases triggered by stress at all stages of fish cultures
for commercial production.

Stress and immune modulation in fish

Lluis Tort
Developmental and Comparative Immunology 35 (2011) 1366–1375

Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered.

Stress is a general term proposed by Hans Selye in 1953 (Selye, 1953) applying to a situation in which a person or an animal is subjected to a challenge that may result in a real or symbolic danger for its integrity. The stress response applies to a wide range of physiological mechanisms, including gene and protein changes, metabolism, energetics, immune, endocrine, neural and even behavioral changes that will first try to overcome that situation and then compensate for the imbalances produced by either the stressor or the consequences generated by the first array of responses.

The stress response is a general and widespread reaction in animals and it
may be assumed that this response has common traits along the phylogenetic tree. Thus, responses such as the fight and flight reaction and therefore the repertoire of energetic arrangements to serve the surplus of activity are observed in all animals. For instance, in terms of molecular responses, the increase in heat shock proteins is observed from invertebrates to fish to humans; the induction of acute phase proteins is also a common trait.

Stress and immune response

Stress and immune response

Stress and immune response. Main events regarding the principal hormones and immune mechanisms involved in acute and chronic stress

A variety of immune changes have been described after applying different kinds of stressors in fish. Hence, both activating and suppressive processes have been described following stress episodes, although the majority of changes often result in deleterious effects. Immediate responses during the activation phase enhance innate humoral immunity such as increased levels of lysozyme and C3 proteins after acute stress or the increase of the number of myeloid-type leukocytes in the peritoneum after intraperitoneal bacterial injection. Moreover, glucocorticoid receptor sites increase in head kidney leukocytes after acute handling stress.

Longer term treatments normally show suppressive effects: Sea bass subjected to crowding stress show reduced immunocompetence, as shown by reduced rates of cytotoxicity and chemiluminescence. A decrease of complement activity, lysozyme levels, agglutination activity and antibody titers is observed after 3 days onwards after repeated stress in sea bream. Stress reduces the number of circulating B-lymphocytes, and decreases the antibody response after immunization in vivo.

Effects of cortisol on cell immune responses

Effects of cortisol on cell immune responses

Effects of cortisol on cell immune responses. The arrow indicates permissive and the cross indicates suppressive. Neuroendocrine response to stress after perception by the sensors of the nervous system involves the immediate secretion of corticosteroid releasing hormone (CRH) by the preoptic nucleus of the hypothalamus. The stimulated CRH receptors in the corticotropic cells of the pituitary gland induce release of adrenocorticotropic hormone (ACTH) into the circulation that subsequently stimulates release of cortisol by the head kidney interrenal cells. ACTH as well as melanocyte-stimulating hormone (α-MSH) are derived from cleavage of the pro-opiomelanocortin gene product. In most fishes this hormone releasing sequence is taking place in seconds for CRH, seconds to minutes for ACTH, and minutes for cortisol. Since the effect of corticosteroids is exerted in most tissues, a number of studies looking at the consequences of cortisol release on the immune system have been performed but less work has been done on its precursors.

It is assumed that the nervous system plays a principal role in stress episodes as the main center for sensing the challenge and developing fight-or-flight responses. At the same time, endocrine networks are responsible for a number of responses related to the subsequent reorganization of energetic resources and modification of metabolism. Finally, the immune system is not only activated very early in the time course response but it has been shown to appear as a main partner in the regulatory network that is able to modulate non-specific immediate responses and modify hormonal activity. Therefore, in summary

  • all three regulatory systems have a role in the building of a stress response
    (b) their interaction modulates and fine tunes the initial response to avoid excessive activation and adapting resources to the specific challenge.
    These interactions will not only serve for any particular stress episode but also for adapting and preparing the response for future challenges.

Neural Input Is Critical for Arcuate Hypothalamic Neurons to Mount Intracellular Signaling Responses to Systemic Insulin and Deoxyglucose Challenges in Male Rats: Implications for Communication Within Feeding and Metabolic Control Networks

Arshad M. Khan, Ellen M. Walker, Nicole Dominguez, and Alan G. Watts
Endocrinology 155: 405–416, 2014

The hypothalamic arcuate nucleus (ARH) controls rat feeding behavior in part through peptidergic

neurons projecting to the hypothalamic paraventricular nucleus (PVH). Hindbrain catecholaminergic

(CA) neurons innervate both the PVH and ARH, and ablation of CA afferents to PVH neuroendocrine

neurons prevents them from mounting cellular responses to systemic metabolic challenges such as insulin or 2-deoxy-D-glucose (2-DG). Here, we asked whether ablating CA afferents also limits their ARH responses to the same challenges or alters ARH connectivity with the PVH. We examined ARH neurons for three features:

(1) CA afferents, visualized by dopamine-β-hydroxylase (DBH)– immunoreactivity;

(2) activation by systemic metabolic challenge, as measured by increased numbers of neurons immunoreactive (ir) for phosphorylated ERK1/2 (pERK1/2);

(3) density of PVH-targeted axons immunoreactive for the feeding control peptides Agouti-related peptide and  α-melanocyte-stimulating hormone (αMSH).
Loss of PVH DBH immunoreactivity resulted in concomitant ARH reductions of DBH-ir and pERK1/2-ir neurons in the medial ARH, where AgRP neurons are enriched. In contrast, pERK1/2 immunoreactivity after systemic metabolic challenge was absent in αMSH-ir ARH neurons. Yet surprisingly, axonal αMSH immune-reactivity in the PVH was markedly increased in CA-ablated animals. These results indicate that

(1) intrinsic ARH activity is insufficient to recruit pERK1/2-ir ARH neurons during systemic metabolic challenges (rather, hindbrain-originating CA neurons are required); and

(2) rats may compensate for a loss of CA innervation to the ARH and PVH by increased expression of αMSH.
These findings highlight the existence of a hierarchical dependence for ARH responses to neural and humoral signals that influence feeding behavior and metabolism.

Acute hypernatremia dampens stress-induced enhancement of long-term potentiation in the dentate gyrus of rat hippocampus

Chiung-Chun Huang, Chiao-Yin Chu, Che-Ming Yeh , Kuei-Sen Hsu
Psychoneuroendocrinology (2014) 46, 129—140

Stress often occurs within the context of homeostatic threat, requiring integration of physiological and psychological demands to trigger appropriate behavioral, autonomic and endocrine responses. However, the neural mechanism underlying stress integration remains elusive. Using an acute hypernatremic challenge (2.0 M NaCl subcutaneous), we assessed whether physical state may affect subsequent responsiveness to psychogenic stressors. We found that experienced forced swimming (FS, 15 min in 25 8C), a model of psychogenic stress, enhanced long-term potentiation (LTP) induction in the dentate gyrus (DG) of the rat hippocampus ex vivo. The effect of FS on LTP was prevented when the animals were adrenalectomized or given mineralocorticoid receptor antagonist RU28318 before experiencing stress. Intriguingly, relative to normonatremic controls, hypernatremic challenge effectively elevated plasma sodium concentration and dampened FS-induced enhancement of LTP, which was prevented by adrenalectomy. In addition, acute hypernatremic challenge resulted in increased extracellular signal regulated kinase (ERK)1/2 phosphorylation in the DG and occluded the subsequent activation of ERK1/2 by FS. Moreover, stress response dampening effects by acute hypernatremic challenge remained intact in conditional oxytocin receptor knockout mice. These results suggest that acute hypernatremic challenge evokes a sustained increase in plasma corticosterone concentration,

Long-term dysregulation of brain corticotrophin and glucocorticoid receptors and stress reactivity by single early-life pain experience in male and female rats

Nicole C. Victoria, Kiyoshi Inoue, Larry J. Young, Anne Z. Murphy
Psychoneuroendocrinology (2013) 38, 3015—3028

Inflammatory pain experienced on the day of birth (postnatal day 0: PD0) significantly dampens behavioral responses to stress- and anxiety-provoking stimuli in adult rats. However, to date, the mechanisms by which early life pain permanently alters adult stress responses remain unknown. The present studies examined the impact of inflammatory pain, experienced on the day of birth, on adult expression of receptors or proteins implicated in the activation and termination of the stress response, including corticotrophin releasing factor receptors (CRFR1 and CRFR2) and glucocorticoid receptor (GR). Using competitive receptor autoradiography, we show that Sprague Dawley male and female rat pups administered 1% carrageenan into the intraplantar surface of the hindpaw on the day of birth have significantly decreased CRFR1 binding in the basolateral amygdala and midbrain periaqueductal gray in adulthood. In contrast, CRFR2 binding, which is associated with stress termination, was significantly increased in the lateral septum and cortical amygdala. GR expression, measured with in situ hybridization and immunohistochemistry, was significantly increased in the paraventricular nucleus of the hypothalamus and significantly decreased in the hippocampus of neonatally injured adults. In parallel, acute stress-induced corticosterone release was significantly attenuated and returned to baseline more rapidly in adults injured on PD0 in comparison to controls.
Collectively, these data show that early life pain alters neural circuits that regulate responses to and neuroendocrine recovery from stress, and suggest that pain experienced by infants in the Neonatal Intensive Care Unit may permanently alter future responses to anxiety- and stress provoking stimuli.

The Impact of Ventral Noradrenergic Bundle Lesions on Increased IL-1 in the PVN and Hormonal Responses to Stress in Male Sprague Dawley Rats

Peter Blandino Jr, CM Hueston, CJ Barnum, C Bishop, and Terrence Deak
Endocrinology 154: 2489–2500, 2013

The impact of acute stress on inflammatory signaling within the central nervous system is of interest because these factors influence neuroendocrine function both directly and indirectly. Exposure to certain stressors increases expression of the proinflammatory cytokine, Il-1 in the hypothalamus. Increased IL-1 is reciprocally regulated by norepinephrine (stimulatory) and corticosterone (inhibitory), yet neural pathways underlying increased IL-1 have not been clarified.
These experiments explored the impact of bilateral lesions of the ventral noradrenergic bundle (VNAB) on IL-1 expression in the paraventricular nucleus of the hypothalamus (PVN) after foot shock. Adult male Sprague Dawley rats received bilateral 6-hydroxydopamine lesions of the VNAB (VNABx) and were exposed to intermittent foot shock. VNABx depleted approximately 64% of norepinephrine in the PVN and attenuated the IL-1 response produced by foot shock. However, characterization of the hypothalamic-pituitary-adrenal response, a crucial prerequisite for interpreting the effect of VNABx on IL-1 expression, revealed a profound dissociation between ACTH and corticosterone.

Specifically, VNABx blocked the intronic CRH response in the PVN and the increase in plasma ACTH, whereas corticosterone was unaffected at all time points examined. Additionally, foot shock led to a rapid and profound increase in cyclooxygenase-2 and IL-1 expression within the adrenal glands, whereas more subtle effects were observed in the pituitary gland.

Together the findings were

1) demonstration that exposure to acute stress increased expression of inflammatory factors more broadly throughout the hypothalamic-pituitary-adrenal axis;

2) implication of a modest role for norepinephrine-containing fibers of the VNAB as an upstream regulator of PVN IL-1; and

3) suggestion of an ACTH-independent mechanism controlling the release of corticosterone in VNABx rats.

Stress and trauma: BDNF control of dendritic-spine formation and regression

M.R. Bennett,  J. Lagopoulos
Progress in Neurobiology 112 (2014) 80–99

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription
are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF
there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress.

Structure of the rodent BDNF gene

Structure of the rodent BDNF gene

Structure of the rodent BDNF gene. Exons are represented as boxes and the introns as lines. Numbers of the exons are indicated in Roman numerals. The coding exon (exon IX) contains two polyadenylation sites (poly A). The start codon (ATG) that marks the initiation of transcription is indicated. The red box shows the region of exon IX coding for the pro-BDNF protein. Some exons, like exon II and IX, contain different transcript variants with alternative splice-donor sites. Also shown is part of the BDNF exon IV sequence in adults with adverse infant experiences showing cytosine methylation (M) at three of the 12 CG dinucleotide sites (numbered with superscripts). See Boulle et al. (2012).

Epigenetic mechanism associated with repression and activation of BDNF exon IV transcription.

Epigenetic mechanism associated with repression and activation of BDNF exon IV transcription.

Epigenetic mechanism associated with repression and activation of BDNF exon IV transcription. The BDNF exon IV displays 12 distinct CpG sites, which can be methylated and interact selectively with MeCp2 to form complexes that repress gene transcription (see also Fig. 1). Histone methyltransferases (HMT) are responsible for adding methyl groups at histone tails (Panel A), whereas histone deacetylases (HDAC) remove acetylation at histone tails (Panel B), both processes that repress gene transcription. Moreover, low levels of nicotinamine adenine dinucleotide (NAD) promote DNA methylation at the BDNF locus. BDNF gene activation is associated with increased histone H3 and H4 acetylation, which is mediated by histone acetyl transferase (HAT) activity. DNA demethylation might be facilitated by growth arrest and DNA damage proteins such as Gadd45b. An increased binding of CREB to its specific binding protein, CREB binding protein (CBP), is also associated with an increase in BDNF gene transcription. See Boulle et al. (2012).

signaling and epigenetic pathways in granule neurons of the dentate gyrus

signaling and epigenetic pathways in granule neurons of the dentate gyrus

Schematic representation of the signaling and epigenetic pathways in granule neurons of the dentate gyrus thought to be involved in the consolidation process of memory formation after a psychologically stressful challenge. Activation of NMDAR results in stimulation of the MAPK/ERK signaling cascade, the AC /PKA cascade and the CaMKII cascade. In conjunction with activated GR these signaling cascades result in the activation of MSK and ERK leading to the formation of dual histone acetylation marks along the c-Fos promoter and subsequently induction of gene transcription. Signaling via CREB also leads to the same outcome. The induction of gene transcription is thought to be instrumental in the consolidation of memory formation in various stressful learning events. See Trollope et al. (2012).

Model for G9a-GLP complex transcriptional activity in the hippocampus

Model for G9a-GLP complex transcriptional activity in the hippocampus

Model for G9a/GLP complex transcriptional activity in the hippocampus during fear memory consolidation. Shown (panels A and B) is the role of G9a/GLP in the regulation of chromatin remodeling during long-term memory consolidation. Regulation of histone lysine methylation mediates active and repressive transcriptional regulation of genes in the hippocampus. The
changes in chromatin structure results in transcriptional gene silencing in the hippocampus. H3K9me2 dimethylation is associated with transcriptional silencing (not shown). The G9a/GLP complex methyltransferase is specific for producing this modification. Abbreviations: Ac, acetylation; M, methylation; MLLI, histone H3 lysine 4 methyltransferase (which regulates memory formation); H3K9me2, histone H3 lysine 9 dimethylation; HAT, histone acetyltransferase; G9a/GLP, G9a/G9a-like protein (GLP) complex methyltransferase.

Modification of serotonin reuptake transport, with inhibitors such as fluoxetine, augments BDNF exon I mRNA levels in the BLA as well as in the hippocampus. This augmentation is lost and replaced by a decrease in BDNF levels if the mice are homozygous for the BDNF Val66Met SNP. A better outcome is obtained for erasing fear memories in PTSD subjects than using D-cycloserine if a combination is used of extinction training with chronic fluoxetine treatment that augments BDNF exon I mRNA.


The following points are suggested by the present review on identifying the changes in dendritic spine synapses in neural networks under stress, the mechanisms that drive these, and how these networks can be reinstated to normality.

Dendritic spines and BDNF

Activation of BDNF leads to the sprouting of dendrites in many areas of the brain, such as CA1 in the hippocampus. As glucocorticoids decrease BDNF expression they decrease dendritic spine density in these areas . Thus activation of both GR and MR with corticosterone leads to an increase in dendritic spine turnover on pyramidal neurons in these areas. In other areas of the brain glucocorticoids do not have this.  Extinction of a fear memory, such as, of the negative effects of opiate withdrawal, involves increases of BDNF mRNA and protein in the ventromedial prefrontal cortex, through the action of CREB at histone H3 of the BDNF exon I transcript promoter with acetylation of the histone. This could be enhanced before extinction training with histone deacetylase inhibitors such as trichostatin A or inhibitors such as U0126 of ERK.
Major risk factors for PTSD are low levels of cortisol in the blood immediately after the trauma occasion; and before the trauma, in peripheral blood mononuclear cells, the presence of high GR numbers, low FKBP5 expression, and high levels of GILZ mRNA. All of these risk factors are involved in the action of cytoplasmic GR in modulating gene transduction, including most likely that for the BDNF gene, as well as regulating the capacity for BDNF itself to act. This emphasis on GR in PTSD is enforced by the observations that there is an association between two polymorphisms in the GR gene (N363S and Bcl1) and PTSD as there is between that of FKBP5 and GILZ on the one hand and the capacity of GR to modulate gene function on the other.

Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning

Dylan Chou, Chiung-Chun Huang, Kuei-Sen Hsu
Experimental Neurology 255 (2014) 19–29

Fear conditioning in animals has been used extensively tomodel clinical anxiety disorders. While individual animals exhibit marked differences in their propensity to undergo fear conditioning, the physiologically relevant mediators have not yet been fully characterized. Here, we demonstrate that C57BL/6 inbred mouse strain subjected to a regimen of chronic social defeat stress (CSDS) can be separated into susceptible and resistant subpopulations that display different levels of fear responses in an auditory fear conditioning  paradigm. Susceptible mice had significantly more c-Fos protein expression
in neurons of the basolateral amygdala (BLA) following CSDS and showed exaggerated conditioned fear responses, while there were no significant differences between groups in innate anxiety- and depressive-like behaviors. Through the use of conditional brain-derived neurotrophic factor (BDNF) knockout strategies, we find that elevated BLA BDNF level following fear conditioning training is a key mediator contributing to determine the levels of conditioned fear responses. Our results also show that relative to susceptible mice, resistant mice had a much faster recovery from conditioned stimuli-induced cardiovascular and corticosterone responses. Systemic administration of norepinephrine reuptake inhibitor atomoxetine increased c-Fos protein expression in BLA neurons following fear conditioning training and promoted the expression of conditioned fear in resistant mice. Conversely, administration of β-adrenergic receptor antagonist propranolol reduced fear conditioning training-induced c-Fos protein expression in BLA neurons and reduced conditioned fear responses in susceptible mice. These findings reveal a novel role for the BDNF signaling within the BLA in mediating individual differences in autonomic, neuroendocrine and behavioral reactivity to fear conditioning.

Melanocortin-4 receptor in the medial amygdala regulates emotional stress-induced anxiety-like behavior, anorexia and corticosterone secretion

Jing Liu, Jacob C. Garza, Wei Li and Xin-Yun Lu
Intl J Neuropsychopharmacology (2013), 16, 105–120.

The central melanocortin system has been implicated in emotional stress-induced anxiety, anorexia and activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the underlying neural substrates have not been identified. The medial amygdala (MeA) is highly sensitive to emotional stress and expresses high levels of the melanocortin-4 receptor (MC4R). This study investigated the effects of activation and blockade of MC4R in the MeA
on anxiety-like behavior, food intake and corticosterone secretion. We demonstrate that MC4R-expressing neurons in the MeA were activated by acute restraint stress, as indicated by induction of c-fos mRNA expression. Infusion of a selective MC4R agonist into the MeA elicited anxiogenic-like effects in the elevated plus-maze test and decreased food intake. Local MeA infusion of SHU 9119, an MC4R antagonist, on the other hand, blocked restraint stress-induced anxiogenic and anorectic effects. Moreover, plasma corticosterone levels were increased by intra-MeA infusion of the MC4R agonist under non-stressed conditions and restraint stress-induced elevation of plasma corticosterone levels was attenuated by pretreatment with SHU 9119 in the MeA. Thus, stimulating MC4R in the MeA induces stress-like anxiogenic and anorectic effects as well as activation of the HPA axis, whereas antagonizing MC4R in this region blocks such effects induced by restraint stress. Together, our results implicate MC4R signaling in the MeA in behavioral and endocrine responses to stress.

The neuroendocrine functions of the parathyroid hormone 2 receptor

Arpád Dobolyi, Eugene Dimitrov, Miklós Palkovits and Ted B. Usdin
Front in Endocr Oct 2012 | Volume 3 | Article 121, 1-10

The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons.TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state
of animals and their fear response, and increases stress-induced analgesia.

TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play
a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation ofTIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders.

Interaction of the Serotonin Transporter-Linked Polymorphic Region and Environmental Adversity: Increased Amygdala-Hypothalamus Connectivity as a Potential Mechanism Linking Neural and Endocrine Hyperreactivity

Nina Alexander, T Klucken, G Koppe, R Osinsky, B Walter, et al.
Biol Psychiatry 2012;72:49–56

Background: Gene by environment (GE) interaction between genetic variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) and stressful life events (SLEs) has been extensively studied in the context of depression. Recent findings suggest increased neural and endocrine stress sensitivity as a possible mechanism conveying elevated vulnerability to psychopathology. Furthermore, these GE mediated alterations very likely reflect interrelated biological processes. Methods: In the present functional magnetic resonance imaging study, amygdala reactivity to fearful stimuli was assessed in healthy male adults (n[1]44),who were previously found to differ with regard to endocrine stress reactivity as a function of 5-HTTLPRSLEs. Furthermore, functional connectivity between the amygdala and the hypothalamus was measured as a potential mechanism linking elevated neural and endocrine responses during stressful/threatening situations. The study sample was carefully preselected regarding 5-HTTLPR genotype and SLEs. Results: We report significant GE interaction on neural response patterns and functional amygdala-hypothalamus connectivity. Homozygous carriers of the 5-HTTLPR S’ allele with a history of SLEs (S’S’/high SLEs group) displayed elevated bilateral amygdala activation in response to fearful faces. Within the same sample, a comparable GE interaction effect has previously been demonstrated regarding increased cortisol reactivity, indicating a cross-validation of heightened biological stress sensitivity. Furthermore, S’S’/high SLEs subjects were characterized by an increased functional coupling between the right amygdala and the hypothalamus, thus indicating a potential link between neural and endocrine hyperreactivity.

Amygdala reactivity to fearful faces as a function of the serotonin transporter-linked polymorphic region (5-HTTLPR)

Amygdala reactivity to fearful faces as a function of the serotonin transporter-linked polymorphic region (5-HTTLPR)

Amygdala reactivity to fearful faces as a function of the serotonin transporter-linked polymorphic region (5-HTTLPR) stressful life events (SLEs). The color bar depicts t values for the gene by environment interaction effect. For illustration reasons, the data were thresholded with a t value at 2.5 (see color bar for exact t values).

We report a significant 5-HTTLPRxSLEs interaction effect on bilateral amygdala reactivity to fearful faces in a sample of healthy male adults. As hypothesized, S’S’/high SLEs individuals appeared to be most reactive, which can be interpreted in terms of elevated amygdala reactivity to briefly presented (phasic) aversive stimuli. Interestingly, we have observed a similar response pattern regarding cortisol reactivity to acute stress within the same sample, indicating a cross-validation of neuroendocrine hyperreactivity to threatening/stressful stimuli as a function of 5-HTTLPRxSLEs.

Thus, our results are in line with findings from a small sample sized (n = 15) study reporting a positive association between amygdala reactivity to fearful faces and SLEs in S allele carriers during an unconscious fear processing condition. In contrast, a study using a comparable paradigm and sample size (n = 44) to our own found amygdala activity in the contrast neutral faces versus fixation to be negatively associated with SLEs in S allele carriers. The authors interpret the latter finding in support of a tonic model, by which SLEs interact with 5-HTTLPR on amygdala resting activation. Similar inconsistencies have been reported regarding the association of 5-HTTLPR and amygdala activation independent of environmental adversity, with studies supporting either a phasic or tonic model. Likewise, increased resting blood perfusion in S allele carriers has been reported in independent studies, whereas the largest study
to date could not replicate these findings.

Functional connectivity between the right amygdala as the seed region

Functional connectivity between the right amygdala as the seed region

  • Functional connectivity between the right amygdala as the seed region

(blue circle, right figure) and the hypothalamus (red circles). The middle figure depicts significant differences in activation patterns between the S’S’/high stressful life events (SLEs) and the L’/low SLEs groups and the left figure displays significant differences between S’S’/high SLEs and S’S’/high SLEs subjects. For illustration reasons, threshold was t =2.5 b (below).
(B) Surface plot of functional connectivity at the z-slice location of the peak coordinate. Voxel intensities are given in t values. 5-HTTLPR, serotonin-transporter-linked polymorphic region.

In conclusion, we report increased amygdala responsivity to aversive stimuli in healthy S’S’/high SLEs subjects who have previously been shown to display elevated cortisol secretion in response to psychosocial stress. Thus, our findings contribute to the current debate on potential mechanisms mediating susceptibility for the development of psychiatric disorders as a function of 5-HTTLPRxSLEs. Moreover, the present study extends previous findings by demonstrating altered functional coupling between the amygdala and the hypothalamus, thus indicating a potential link between threat/stress related neural and endocrine alterations associated with 5-HTTLPR x SLEs.

Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter Environment Risk Factor for Anxiety and Depression


Valeria Carola, Giovanni Frazzetto, Tiziana Pascucci, Enrica Audero, et al.
Biol Psychiatry 2008;63:840–846

Background: A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse.

Methods: We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene environment effects.

Results: Mice experiencing low maternal care showed deficient ϒ-aminobutyric acid–A receptor binding in the amygdala and 5-HTT  heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT environment risk factor.

Conclusions: These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF  as a molecular substrate of this risk factor. In summary, we have produced a mouse model of the 5-HTT environment risk factor for human depression and have used this model to identify molecular substrates underlying this risk factor.

Elevated GABA-A receptor expression in amygdala, decreased 5-HT turnover in hippocampus, and enhanced BDNF expression in hippocampus each correlated significantly with the behavioral phenotype seen in our mice. In particular, increased expression of BDNF in CA1 pyramidal neurons was found in mice with reduced 5-HTT function and exposed to low maternal care. This defect was accompanied by an increased bias in the response to threatening cues as assessed by ambiguous cue fear conditioning.

Our data suggest that alterations in hippocampal gene expression and function underlie at least part of the interaction between 5-HTT and rearing environment and point to a role for this structure in the increased anxiety and depression-related behavior that is a risk factor for major depression.

Gene—environment interactions predict cortisol responses after acute stress: Implications for the etiology of depression

Nina Alexander, Yvonne Kuepper, Anja Schmitz, Roman Osinsky, et al.
Psychoneuroendocrinology (2009) 34, 1294—1303

Background: Growing evidence suggests that the serotonin transporter polymorphism (5-HTTLPR) interacts with adverse environmental influences to produce an increased risk for the development of depression while the underlying mechanisms of this association remain largely unexplored. As one potential intermediate phenotype, we investigated alterations of hypothalamic—pituitary—adrenal (HPA) axis responses to stress in individuals with no history of psychopathology depending on both 5-HTTLPR and stressful life events.

Methods: Healthy male adults (N = 100) were genotyped and completed a questionnaire on severe stressful life events (Life Events Checklist). To test for gene-by-environment interactions on endocrine stress reactivity, subjects were exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol levels were obtained at 6 time points prior to the stressor and during an extended recovery period.

Results: Subjects homozygous for the s-allele with a significant history of stressful life events exhibited markedly elevated cortisol secretions in response to the stressor compared to all other groups, indicating a significant gene-by-environment interaction on endocrine stress reactivity. No main effect of either 5-HTTLPR (biallelic and triallelic) or stressful life events on cortisol secretion patterns appeared.

Conclusion: This is the first study reporting that 5-HTTLPR and stressful life events interact to predict endocrine stress reactivity in a non-clinical sample. Our results underpin the potential moderating role of HPA-axis hyper-reactivity as a premorbid risk factor to increase the vulnerability for depression in subjects with low serotonin transporter efficiency and a history of severe life events.

The immune system and developmental programming of brain and behavior

Staci D. Bilbo, Jaclyn M. Schwarz
Frontiers in Neuroendocrinology 33 (2012) 267–286

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone–behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition.

Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia

Darrick T. Balua, Joseph T. Coyle
Neuroscience and Biobehavioral Reviews 35 (2011) 848–870

Schizophrenia is a severe mental illness that afflicts nearly 1% of the world’s population. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity. Although the etiology of schizophrenia is unknown, it appears to be a developmental disorder involving the interaction of a potentially large number of risk genes, with no one gene producing a strong effect except rare, highly penetrant copy number variants. The purpose of this review is to detail how putative schizophrenia risk genes (DISC-1, neuregulin/ErbB4, dysbindin, Akt1, BDNF, and the NMDA receptor) are involved in regulating neuroplasticity and how alterations in their expression may contribute to the disconnectivity observed in schizophrenia. Moreover, this review highlights how many of these risk genes converge to regulate common neurotransmitter systems and signaling pathways. Future studies aimed at elucidating the functions of these risk genes will provide new insights into the pathophysiology of schizophrenia and will likely lead to the nomination of novel therapeutic targets for restoring proper synaptic connectivity in the brain in schizophrenia and related disorders.

Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction

Darrick T. Balu, Joseph T. Coyle
Brain Research 1392 (2011 ) 1–7

The N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) are ionotropic glutamate receptors responsible for excitatory neurotransmission in the brain. These excitatory synapses are found on dendritic spines, with the abundance of receptors concentrated at the postsynaptic density (PSD).
We utilized two genetic mouse models, the serine racemase knockout (SR−/−) and the glycine transporter subtype 1 heterozygote mutant (GlyT1+/−), to determine how constitutive NMDAR hypo- and hyperfunction, respectively, affect the glutamate receptor composition of the PSD in the hippocampus and prefrontal cortex (PFC).

Using cellular fractionation, we found that SR−/− mice had elevated protein levels of NR1 and NR2A NMDAR subunits specifically in the PSD-enriched fraction from the hippocampus, but not from the PFC. There were no changes in the amounts of AMPAR subunits (GluR1, GluR2), or PSD protein of 95 kDa (PSD95) in either brain region. GlyT1+/− mice also had elevated protein expression of NR1 and NR2A subunits in the PSD, as well as an increase in total protein. Moreover, GlyT1+/− mice had elevated amounts of GluR1 and GluR2 in the PSD, and higher total amounts of GluR1. Similar to SR−/− mice, there were no protein changes observed in the PFC. These findings illustrate the complexity of synaptic adaptation to altered NMDAR function.

Interleukin-1 (IL-1): A central regulator of stress responses

Inbal Goshen, Raz Yirmiya
Frontiers in Neuroendocrinology 30 (2009) 30–45

Ample evidence demonstrates that the pro-inflammatory cytokine interleukin-1 (IL-1), produced following exposure to immunological and psychological challenges, plays an important role in the neuroendocrine and behavioral stress responses. Specifically, production of brain IL-1 is an important link in stress induced activation of the hypothalamus-pituitary-adrenal axis and secretion of glucocorticoids, which
mediate the effects of stress on memory functioning and neural plasticity, exerting beneficial effects at low levels and detrimental effects at high levels. Furthermore, IL-1 signaling and the resultant glucocorticoid secretion mediate the development of depressive symptoms associated with exposure to acute and chronic stressors, at least partly via suppression of hippocampal neurogenesis. These findings indicate
that whereas under some physiological conditions low levels of IL-1 promote the adaptive stress responses necessary for efficient coping, under severe and chronic stress conditions blockade of IL-1 signaling can be used as a preventive and therapeutic procedure for alleviating stress-associated neuropathology
and psychopathology.

IL-1 mediates stress-induced activation of the HPA axis

IL-1 mediates stress-induced activation of the HPA axis

IL-1 mediates stress-induced activation of the HPA axis. Immunological and
psychological stressors increase the levels of IL-1 in various brain areas, including
several brain stem nuclei, the hypothalamus and the hippocampus. In turn, IL-1
induces the secretion of CRH from the hypothalamic paraventricular nucleus (PVN),
ACTH from the pituitary and glucocorticoids from the adrenal. Following immunological
stressors, peripheral IL-1 can directly influence brain stem nuclei, such as
the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM) as well as the
hypothalamus via penetration to adjacent circumventricular organs, (the area
postrema (AP) and the organum vasculosum of the lamina terminalis (OVLT),
respectively). Concomitantly, IL-1 in the periphery can activate vagal afferents,
which innervate and activate the NTS and VLM. These nuclei project to the
hypothalamus, in which the secretion of NE induces further elevation of IL-1 levels,
possibly by microglial activation. Psychological stressors can also activate the NTS
and VLM, either by intrinsic brain circuits or via vagal feedback from physiological
systems (e.g., the cardiovascular system) that are stimulated by the sympathetic
nervous system. Similarly to their role in immunological stress, the NTS and VLM
then elevate hypothalamic IL-1 levels, stimulating the CRH neurons.

The inverted U-shaped effect of IL-1 on memory and plasticity is mediated by glucocorticoids

The inverted U-shaped effect of IL-1 on memory and plasticity is mediated by glucocorticoids

The inverted U-shaped effect of IL-1 on memory and plasticity is mediated by glucocorticoids. The influence of IL-1 on memory and plasticity follows an inverted Ushape pattern, i.e., learning-associated increase in IL-1 levels is needed for memory formation (green), whereas any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in memory and plasticity impairment (red). Low dose GCs can also facilitate memory, whereas chronic or severe stressors, as well as high GC levels, can impair memory and neural plasticity. Studies on the implications of the interaction between stress, IL-1 and GCs on memory
and plasticity show that IL-1 mediates the detrimental effects of stress on memory, and that GCs are involved in both the detrimental and the beneficial effects of IL-1 on memory formation. Based on these studies, the following model is proposed: stressful stimuli induce an increase in brain IL-1 levels, which in turn contributes to the activation of the HPA axis. Subsequently, the secretion of GCs affects memory and plasticity processes in an inverted U-shaped pattern.

Immune modulation of learning, memory, neural plasticity and neurogenesis

Raz Yirmiya ⇑, Inbal Goshen
Brain, Behavior, and Immunity 25 (2011) 181–213

Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis.
These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones
(e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFa, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory
cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules, facilitating many forms of neuropathology
associated with normal aging as well as neurodegenerative and neuropsychiatric diseases.

It is now firmly established that the immune system can modulate brain functioning and behavioral processes. This modulation is exerted by plasticity are among the most important aspects of brain functioning that are modulated by immune mechanisms. The aim of the present review is to present a comprehensive and integrative view of the complex dual role of the immune system in learning,memory, neural plasticity and neurogenesis. The first part of the review will focus on the physiological
beneficial effects of the immune system under normal, quiescent conditions. Under such conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate neuroplasticity and neurogenesis, promoting learning, memory, and hippocampal long-term potentiation (LTP). The second part of the review will focus on the detrimental effects of inflammatory conditions induced by infections and injury as well as severe or chronic stress, demonstrating that under such
conditions the delicate physiological balance between immune and neural processes is disrupted, resulting in neuronal hyperexcitability, hormonal aberrant ions, reduced neurotrophic factors production and suppressed neurogenesis, leading to impairments in learning, memory and neuroplasticity.

A systemic model of the beneficial role of immune processes in behavioral and neural plasticity

A systemic model of the beneficial role of immune processes in behavioral and neural plasticity

A systemic model of the beneficial role of immune processes in behavioral and neural plasticity. Learning, memory and synaptic plasticity involve neural activation of hippocampal circuits by glutamatergic inputs that originate mainly in multiple cortical areas. Long-term memory consolidation also requires emotional (limbic) activation (particularly of the amygdala and hypothalamus), inducing a mild stressful condition, which in turn results in HPA axis and sympathetic nervous system (SNS) stimulation. The peripheral organs that are the targets of these systems (e.g., the adrenal glad, heart, blood vessels and gastrointestinal (GI) tract), in turn, send afferent inputs to the brain that culminate in stimulation of receptors for glucocorticoids, norepinephrine, dopamine and serotonin on hippocampal cells. These inputs are critical for memory consolidation, neural plasticity and neurogenesis. Furthermore, these inputs induce the production of IL-1, and possibly other cytokines, chemokines and immune mediators in the hippocampus, as well as in other brain areas (such as the hypothalamus and brain stem) that are critically important for neurobehavioral plasticity. Moreover, these cytokines, in turn further activate the HPA axis and SNS, thus participating in a brain-to-body-to-brain reverberating feedback loops.

Chemokines and the hippocampus: A new perspective on hippocampal plasticity and vulnerability

Lauren L. Williamson, Staci D. Bilbo
Brain, Behavior,and Immunity 30(2013)186–194

Chemokines roles within the hippocampus

Chemokines roles within the hippocampus

Chemokines have important roles within the hippocampus and may modulate plasticity and vulnerability within this unique structure. Neuroimmune signaling can occur across the blood-brain-barrier (BBB) via endothelial cells, astrocytes, and microglia within the BBB that recapitulate the immune signal from the periphery by secreting their own cohort of cytokines into the brain. Chemokines recruit cells to sites of injury as well . Microglia receive input from neurons via several membrane-bound and secreted factors, including neuronal CX3CL1 (fractalkine) and its receptor, CX3CR1, on microglia, which allow direct neuroimmune interaction. CXCL12 is released from vesicles concomitantly with GABA from basket cells onto immature neurons in the DG granule cell layer.  In the healthy brain, chemokines may modulate neuronal signaling during behavior, though this phenomenon remains to be explored. The spatial and temporal signaling and cellular sources of chemokines and their receptors are critical for understanding

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Pain Management Drug Market: Insight Pharma Reports

Reporter: Aviva Lev-Ari, PhD, RN


UPDATED on 4/10/2018

Pharma turns to new pain options amid opioid crisis



Announcement by

Lisa Scimemi, MBE, MSM


Insight Pharma Reports

250 First Avenue, Suite 300

Needham, MA 02494

I wanted to make you aware of these new reports available from


  • Global Pain Management Devices Market 2014-2018
  • Chronic Pain – Pipeline Review
  • Global Pain Management Drugs Market 2014-2018
  • Cancer Pain – Pipeline Review
  • Acute Pain Global Clinical Trials Review
  • Pain Management Therapeutics Market to 2019
  • Inflammatory Pain – Pipeline Review


All these reports are available thru Insight Pharma Reports.  If you are looking for a specific topic not

listed above, contact us and we can search our network of publishers for a report on the topic are you

are looking for.


If you have any questions, or would like to reserve your copy of one of these reports, contact me today.


Thank you.


Lisa Scimemi, MBE, MSM


Insight Pharma Reports

250 First Avenue, Suite 300

Needham, MA 02494



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Cancer Symptom Science: On the Mechanisms underlying the Expression of Cancer-related Symptoms

Reporter: Aviva Lev-Ari, PhD, RN

Symptom Research Hosts Panel on Developing Strategies for Reducing Cancer Treatment-Related Toxicities and Symptoms

There is little recognition of the large numbers of patients and survivors who are affected by severe symptoms, and insufficient industry interest in developing and testing agents that can address these problems. In contrast to the rapid progress in curative therapies, little systematic research is being conducted on the mechanisms that cause treatment-related symptoms, developing and exploiting preclinical animal models of these symptoms, phase 1-2 studies of symptom prevention and management, or developing an evidence base for new and existing symptom-focused interventions through the clinical trials groups.

In March 2011, the Department of Symptom Research and the Friends of Cancer Research convened stakeholders in cancer research, industry, regulation, and advocacy to identify the challenges that have prevented progress in reducing treatment-related symptom burden, to develop a list of strategic steps to meet these challenges, and to develop a white paper to identify how to implement these steps.

Cancer Symptom Science: Measurement, Mechanisms, and Management

Edited by Charles S. Cleeland, Michael J. Fisch, and Adrian J. Dunn

Cancer Symptom Science - the book


Cancer Symptom Science is the first interdisciplinary compilation of research on the mechanisms underlying the expression of cancer-related symptoms. It presents innovations in clinical, animal and in vitro research, research methods in brain imaging, and statistical-descriptive approaches to understanding the mechanistic basis of symptom expression. It also provides perspectives from patients, government and industry. By collecting and synthesizing the developing threads of new approaches to understanding cancer-related symptoms, the book promotes a pioneering framework for merging behavioral and biological disciplines to clarify mechanisms of symptom evolution, incorporating new technologies, testing novel agents for symptom control, and improving patient functioning and quality of life both during and after cancer treatment.

The editorial team includes MD Anderson faculty Charles Cleeland, PhD, chair of the Department of Symptom Research and Michael Fisch, MD, MPH, chair of the Department of General Oncology; and Adrian Dunn, PhD, of The University of Hawaii at Manoa. The book is targeted toward surgical, clinical and medical oncologists, nurses, academic researchers, fellows and nursing students, and pharmaceutical companies developing new agents to control symptom expression.

Cancer Symptom Science is available from Cambridge University Press and at bookstores online.

MD Anderson Publications Focus on Symptom Research

All links will open a PDF document.

Symptom Assessment Tools

Brief Pain Inventory  |   M. D. Anderson Symptom Inventory   |   Brief Fatigue Inventory

A symptom is a sensation or perception of change related to health function experienced by an individual. Symptoms, such as fatigue, pain and nausea, may be classified based on their severity and perceived impact on function. Symptoms add to the burden of having a chronic disease, such as cancer, and affect virtually all aspects of life. They interfere with a person’s mood, level of activity and ability to relate to others.

The study of symptoms has consisted primarily of descriptive studies of self-report from patients at specific stages of specific types of cancer. Such patient-reported outcomes (PROs) have been recognized by the US Food and Drug Administration as legitimate primary outcome variables for clinical trials.

The Department of Symptom Research has been working since 1979 to design PRO assessment tools for symptoms experienced by cancer patients to determine their severity, and how they affect quality of life.

The Brief Pain Inventory (BPI)

The Brief Pain Inventory (BPI) was developed in 1989 by Dr. Charles Cleeland for rapid assessment of the severity and impact of pain in cancer patients. The BPI has since been translated into more than three dozen languages, and is widely used in both research and clinical settings.

BPI User’s Guide addressing FDA requirements for use of patient-reported outcomes in clinical trials is now available.

The M. D. Anderson Symptom Inventory (MDASI)

The M. D. Anderson Symptom Inventory (MDASI) is used to assess multiple symptoms experienced by cancer patients and the interference with daily living caused by these symptoms. The MDASI is available in both paper-and-pencil and interactive voice response (IVR) formats, both of which are equally effective.

MDASI User’s Guide addressing FDA requirements for use of patient-reported outcomes in clinical trials is now available.

The MDASI-IVR combines the use of touch-tone telephones with computers and the Internet to follow symptoms while the patient is away from the hospital. The MDASI-IVR offers several benefits: (1) missing data are minimized, especially in longitudinal studies; (2) the IVR provides more accurate real-time symptom assessment data at expected time points; and (3) the availability of immediate feedback through the IVR system could allow caregivers to address severe symptoms more effectively.

The Brief Fatigue Inventory (BFI)

The Brief Fatigue Inventory (BFI) is used to rapidly assess the severity and impact of cancer-related fatigue. An increasing focus on cancer-related fatigue emphasized the need for sensitive tools to assess this most frequently reported symptom. The six inventory items correlate with standard quality-of-life measures.

Ease of Use and Readability

Our symptom assessment tools are understandable even by grade-school children, according to the Flesch scoring systems described below.

Flesch Reading Ease score: Rates text on a 100-point scale; the higher the score, the easier it is to understand the document. Most standard documents aim for a score of approximately 60 to 70.

Flesch-Kincaid Grade Level score: Rates text on a U.S. grade-school level. For example, a score of 8.0 means that an eighth grader can understand the document. Most standard documents aim for a score of approximately 7.0 to 8.0.


Flesch Reading Ease Flesch-Kincaid Grade Level
BPI (short form) 83.5 5.1
BFI 70.7 6.4
MDASI 82.3 3.6


The simplicity of the tools facilitates cross-cultural studies of pain and other patient-reported cancer-related symptoms. Validation studies have not been conducted using our assessment tools in the pediatric population, aged 18 years and younger.

Related News

Symptom Research hosts national colloquium on developing strategies for reducing cancer treatment-related toxicities and symptoms. Read more…

 Cancer Symptom Science

Announcing the publication of Cancer Symptom Science, an interdisciplinary, first-of-its-kind compilation of research on the mechanisms underlying the expression of cancer-related symptoms. Read more…

Old Drugs, New Possibilities (Conquest, Fall 2008)

Symptom Research Awarded NIH P01 Grant (Division of Internal Medicine Newsletter, Summer 2008)

Symptom Research and Psychometrics(Network, Summer 2008)

Resources & Links

Michael J. Fisch, MD, MPH, FACP, FAAHPM

Present Title & Affiliation

Primary Appointment

Chair, Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Bio Statement

Michael J. Fisch, MD, MPH, is Professor and Chair of the Department of General Oncology and Medical Director of the Community Clinical Oncology Program in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, TX. He earned his MD from the University of Virginia School of Medicine and his master’s in Public Health from Indiana University in Bloomington, IN. He completed a residency in Internal Medicine at University of Virginia and fellowships in Hematology/Oncology and general internal medicine (Health Services Research) at Indiana University. He is board certified in Internal Medicine, Medical Oncology, and Hospice and Palliative Medicine. Dr. Fisch is a fellow of both the American College of Physicians and the American Academy of Hospice and Palliative Medicine.

Dr. Fisch’s research interests include palliative care, symptom management, and health care disparities. He has been published in the Journal of Clinical Oncology, the Journal of the National Cancer Institute, and numerous other peer-reviewed journals. He has also authored or co-authored several book chapters and books and serves as Editor in Chief for the Journal of Supportive Oncology. He has been an invited speaker at many national and international conferences.  He is an active blogger for the American Society of Clinical Oncology (ASCO) and for MD Anderson, and he is active on twitter as @fischmd. Dr. Fisch is currently the Chair of the Symptom Management Committee of ECOG-ACRIN and Co-Chair of the Symptom Management and Quality of Life Steering Committee for the National Cancer Institute.

Education & Training

Degree-Granting Education

1997 Indiana University, Bloomington, IN, MPH, Health Education
1990 University of Virginia, Charlottesville, VA, MD, Clinical Medicine


Board Certifications


1/2008 ABIM Hospice and Palliative Medicine
1/2003 American Board of Hospice and Palliative Medicine
1/1997 Medical Oncology
1/1993 Internal Medicine


Selected Publications

Peer-Reviewed Original Research Articles

1. Parker PA, Urbauer D, Fisch MJ, Fellman B, Hough H, Miller J, Lanzotti V, Whisnant M, Weiss M, Fellenz L, Bury M, Kokx P, Finn K, Daily M, Cohen L. A Multi-Site, Community Oncology-Based Randomized Trial of a Brief Educational Intervention to Increase Communication Regarding Complementary and Alternative Medicine. Cancer, 7/2013. e-Pub 9/2013. NIHMSID: NIHMS494226.
2. Mendoza TR, Zhao F, Cleeland CS, Wagner LI, Patrick-Miller LJ, Fisch MJ. The Validity and Utility of the M.D. Anderson Symptom Inventory in Patients with Breast Cancer: Evidence From The Symptom Outcomes and Practice Patterns Data From the Eastern Cooperative Oncology Group. Clin Breast Cancer. e-Pub 6/2013. PMCID: PMC3775936.
3. Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ. L-Carnitine Supplementation for the Management of Fatigue in Patients With Cancer: An Eastern Cooperative Oncology Group Phase III, Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Oncol 30(31):3864-9, http://www.ncbi.nlm.nih.gov/pubmed/22987089, 11/2012. PMCID: PMC3478577.
4. Dizon D, Graham D, Thompson M, Johnson L, Johnston C, Fisch M, Miller R. Practical Guidance: The Use of Social Media in Oncology Practice. J Oncol Pract 8(5):114-24, 9/2012. e-Pub 7/2012. PMCID: PMC3439237.
5. Hwang JP, Fisch MJ, Zhang H, Kallen MA, Routbort MJ, Lal L, Vierling JM, Suarez-Almazor ME. Low rates of hepatitis B virus screening at the onset of chemotherapy. J Oncol Pract 8(4):32-9, 7/2012. e-Pub 6/2012. PMCID: PMC3396827.
6. Lal LS, Zhuang A, Hung F, Feng C, Arbuckle R, Fisch MJ. Evaluation of drug interactions in patients treated with antidepressants at a tertiary care cancer center. Support Care Cancer 20(5):983-9, 5/2012. e-Pub 4/2011. PMID: 21519946.
7. Fisch MJ, Lee JW, Weiss M, Wagner LI, Chang VT, Cella D, Manola JB, Minasian LM, McCaskill-Stevens W, Mendoza TR, Cleeland CS. Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer. J Clin Oncol, 4/2012. PMCID: PMC3383175.
8. Ritchie CS, Kvale E, Fisch MJ. Multimorbidity: an issue of growing importance for oncologists. J Oncol Pract 7(37):371-4, 2011. PMCID: PMC3219463.


1. Tevaarwerk AJ, Lee JW, Sesto ME, Buhr KA, Cleeland CS, Manola J, Wagner Ll, Chang VT, Fisch MJ. Employment outcomes among survivors of common cancers: the Symptom Outcomes and Practice Patterns (SOAPP) study. J Cancer Surviv 7(2):191-202, 6/2013. PMCID: PMC3638888.
2. Hwang J, Fisch M, Zhang H, Kallen M, Routbort M, Lal L, Vierling J, Suarez-Almazor M. Low Rates of Hepatitis B Virus Screening at the Onset of Chemotherapy. Journal of Oncology Practice 8(4):32-9, 6/2012. e-Pub 6/2012. PMCID: PMC23180996.
3. Chang VT, Zhao F, Tevaarwerk A, Mitchell EP, Patterson E, Ritchie C, Manola J, Wagner LI, Fisch MJ. Determinants of driving in cancer patients: an analysis for SOAPP (ECOG E2Z02: Symptom Outcomes and Practice Patterns)(MASCC Annual Meeting). Support Care Cancer 20(S151) (#639), 2012.
4. Zhao F, Chang VT, Cleeland C, Cleary JF, Mitchell EP, Patterson E, Wagner LI, Fisch MJ. Determinants of pain changes in ambulatory cancer patients by baseline pain severity: An analysis from ECOG E2Z02 (SOAPP Study)(MASCC Annual Meeting). Support Care Cancer 20(S151) (#638), 2012.

Last updated: 10/31/2013




Cancer Symptom Science

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ISBN: 9780521869010Publisher: Cambridge Year of publishing: 2010   Format:  HardcoverNo of Pages: 376        Language: English

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Overview: Cancer Symptom Science
Cancer Symptom Science is the first interdisciplinary compilation of research on the mechanisms underlying the expression of cancer-related symptoms. It presents innovations in clinical, animal and in vitro research, research methods in brain imaging, and statistical-descriptive approaches to understanding the mechanistic basis of symptom expression. This volume also provides perspectives from patients, government and industry. By collecting and synthesizing the developing threads of new approaches to understanding cancer-related symptoms, the book promotes a pioneering framework for merging behavioral and biological disciplines to clarify mechanisms of symptom evolution, incorporating new technologies, testing novel agents for symptom control, and improving patient functioning and quality of life both during and after cancer treatment. With an expert editorial team led by Charles S. Cleeland, an internationally-recognized leader in cancer pain assessment and treatment, this is essential…Read more »
About the author: Charles S. Cleeland , Michael J. Fisch , Adrian J. Dunn
Charles S. Cleeland is McCullough Professor of Cancer Research and Chair of the Department of Symptom Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. Michael J. Fisch, M.D., MPH is Chair of the Department of General Oncology in the Division of Cancer Medicine at the University of Texas M. D. Anderson Cancer Center. Dr Fisch is a national leader in symptom management and survivorship care. His research and clinical work in this area focuses on the assessment and management of patients with complex symptom problems from the time of diagnosis, through treatment, during survivorship and at the end of life. As medical director of the M. D. Anderson Community Clinical Oncology Program Research Base, Dr Fisch also oversees a network of M. D. Anderson managed clinical trials aimed at cancer control, prevention and therapy implemented and conducted efficiently in a community environment. Adrian J. Dunn is Professor of Psychology, Pacific Biosciences Research… Read more »

Other related article published on this Open Access Online Scientific Journal, include the following:

Dr. Lev-Ari, commissioned Dr. Karra in June 2012 to curate the following article:

The Genetics of Pain: An Integrated Approach

Dr. V. S. Karra, Ph.D.


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Museums Faulted on Restitution of Nazi-Looted Art

Reporter: Aviva Lev-Ari, PhD,RN



Heirs Fight Museums to Reclaim Art: Marty Grosz, the son of German artist George Grosz, seeks the return of some of his father’s works that were acquired by the Museum of Modern Art in New York.


Published: June 30, 2013

Not until 1998, when 44 nations including the United States signed the groundbreaking Washington Principles on Nazi-Confiscated Art, did governments and museums formally embrace the idea that they have a special responsibility to repair the damage caused by the wholesale looting of art owned by Jews during the Third Reich’s reign.

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Estate of George Grosz/Licensed by VAGA, New York; Museum of Modern Art

George Grosz’s heirs want MoMA to return “Poet Max Herrmann-Neisse.”

Now, 15 years later, historians, legal experts and Jewish groups say that some American museums have backtracked on their pledge to settle Holocaust recovery claims on the merits, and have resorted instead to legal and other tactics to block survivors or their heirs from pursuing claims.

In recent years judges have dismissed several cases after museums argued that recovery claims had been filed too late. California legislators were so disturbed by one blocked claim there that they passed a law in 2010 to help Nazi-era (and other) claimants avoid tripping over legal deadlines.

In some of the cases, museums like the Detroit Institute of Arts, the Toledo Museum of Art in Ohio, the Museum of Fine Arts in Boston and the Solomon R. Guggenheim Museum have tried to deter claimants from filing suit by beating them to the courthouse and asking judges to declare the museums the rightful owners.

Critics also charge that museums have not followed their own guidelines, which urge them to be forthcoming with provenance information that could help people trace the history of a contested work of art.

“The response of museums has really been lamentable,” said Jonathan Petropoulos, the former research director for art and cultural property for the Presidential Advisory Commission on Holocaust Assets, who has been hired by claimants to do research. “It is now so daunting for an heir to go forward.”

The question of whether museums are deciding claims on the merits has recently been pushed to center stage again by a series of law journal articles, legal forums and rulings in the United States and abroad. At stake in this emotional debate are the fate of valuable works of art, the reputations of elite cultural institutions and the legal issue of whether the American judicial system is capable of addressing restitution claims.

Both the Association of Art Museum Directors and the American Alliance of Museumsinsist that their members consistently follow ethical guidelines requiring them to respond “quickly and scrupulously” to restitution requests.

Christine Anagnos, executive director of the museum directors association, said its members were committed “to resolving questions about the status of objects in their custody.” Most cases, she said, are resolved through negotiation before claimants feel compelled to file suit.

Museum officials also say they turn to procedural tactics like invoking time limits only after they have carefully researched a claim and concluded that it is unfounded.

But Stuart E. Eizenstat, a former special State Department envoy who negotiated the Washington Principles, said museums have adopted a harder line in the last seven years or so, partly in response to some court victories by art institutions and waning pressure from the government.

“The essence of the Washington Principles comes down to one sentence,” he said. “Let decisions be made on the merits of the case rather than technical defenses.”

No one disputes that, even with databases that list looted art, it takes considerable effort and money to track artworks from Nazi-occupied countries, which typically have gaping holes in their provenance.

There is also agreement that not all claims are valid, which requires that museum directors respond cautiously to safeguard their collections.

Simon J. Frankel, a lawyer who has represented the Museum of Fine Arts in Boston, pointed out in a recent law journal article that since 2010, when the museum went to court to block a Nazi-era restitution claim, it has settled with the heirs of two Jewish art dealers and returned a 14th-century embroidered panel to a museum in Trento, Italy.

Neither side can agree on how many people have approached American museums with restitution claims. The museum directors association, which emphasizes that few cases end up before a judge, lists two dozen cases where institutions, including the Detroit Institute of Arts, returned art to individual heirs without going to court.

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But critics, including the Holocaust Art Restitution Project and the Commission for Art Recovery, say problems arise in the less straightforward cases, where documentation is missing or it is unclear whether Jewish owners freely parted with a work of art or were coerced by the Nazi authorities into selling it for a pittance.

All rights reserved, Estate of George Grosz,/Licensed by VAGA, New York; Image courtesy of Museum of Modern Art

George Grosz’s “Self-Portrait With Model” (1928), at MoMa, is sought by his heirs.

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All rights reserved, Estate of George Grosz,/Licensed by VAGA, New York; Image courtesy of Museum of Modern Art

Grosz’s “Republican Automatons” (1920) is also in dispute.

Mr. Eizenstat is among those who have long argued that the courts are inherently ill suited to resolving restitution cases and that to avoid litigation the United States should create an independent mediation board, as several European countries have. This spring, a New York chapter of the Federal Bar Association put forward a resolution calling for the creation of an American commission along those lines.

Douglas Davidson, the State Department’s current special envoy for Holocaust issues, said at a conference at The Hague in November that “alternatives to litigation are preferable,” but he conceded that a similar American commission is unlikely to emerge. One major obstacle is that whereas in Europe, museums are typically government-owned, most American museums are privately run, making it difficult to mandate compliance.

Such panels are not necessarily insulated from criticism in any case. The Dutch Restitutions Committee, for example, drew criticism last month after it ruled that the interest of two museums in retaining paintings outweighed the heirs’ interest in restitution.

Raymond Dowd, a partner at the Manhattan firm Dunnington, Bartholow & Miller who often handles restitution claims, complains that museums often review the evidence and decide on their own if a case is valid. Museums often fail to make their original research on a work’s provenance or sale available or to submit the scholarship to peer review, he added.

He cited the case of a family that is seeking to recover art once owned by Fritz Grunbaum, a popular Viennese cabaret performer who died at a concentration camp. He said that 10 American museums including the Allen Memorial Art Museum at Oberlin College have works by Egon Schiele that were listed on a 1938 German government inventory created after Mr. Grunbaum was shipped to Dachau. Some of the museums failed to provide full information about the provenance of the works, he said, and the Allen did not even list Mr. Grunbaum in the Schiele’s provenance.

Andria Derstine, the Allen’s director, said in an e-mail that the museum had cooperated with Mr. Dowd’s requests for information and that it has concluded after its own investigation that the claim had no merit. It did revise its online listing last month to reflect that Mr. Grunbaum once owned the Schiele.

For years, the family of the artist George Grosz has fought to recover three works from the Museum of Modern Art, arguing they were the subject of a forced sale after Grosz fled the Nazis in 1933.

A federal judge dismissed the Groszes’ lawsuit in 2011, citing the statute of limitations. Before the case landed in court, the museum hired researchers at Yale University and the former United States attorney general Nicholas deB. Katzenbach (who died in 2012) to review their evidence. Katzenbach concluded that Grosz’s Jewish dealer, Alfred Flechtheim, had fair title to the works and freely sold them. The Groszes’ own experts, though, challenged his report and declared that Flechtheim was forced to flee Germany after his Düsseldorf gallery was “Aryanized” in 1933 and given to a Nazi Party member.

That interpretation was affirmed in April by a ruling from the German government’s advisory commission on plundered art in an unrelated case involving the Museum Ludwig in Cologne. While there is “an absence of concrete evidence,” the commission concluded that on balance, “it is to be assumed that Alfred Flechtheim was forced to sell the disputed painting because he was persecuted.”

Margaret Doyle, a spokeswoman for MoMA, said the museum has no interest in retaining works to which it does not have clear title. “After years of extensive research,” she said, “including numerous conversations with Grosz’s estate, it was evident that we did in fact have good title to the works by Grosz in our collection and therefore an obligation to the public to defend our ownership appropriately.”

But George Grosz’s son Martin, 83, points to a letter his father wrote in 1953 after seeing one of the works, “The Poet Max Herrmann-Neisse,” hanging at MoMA: “Modern Museum exhibits a painting stolen from me (I am powerless against that) they bought it from someone, who stole it.”

“I can remember talking with my father about it,” he said of the painting.

“He was very reluctant to in any way assail or complain about the treatment he got from anybody in the United States,” Mr. Grosz said, explaining why his father never fought to recover the work.

When refugees complained, Mr. Grosz said, his father would respond: “You should kiss the ground you’re walking on because they let you in.”


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