Hypersensitivity to pain produced by early life stress is worsened by later stress exposure

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Hypersensitivity to pain produced by early life stress is worsened by later stress exposure Reports new study in Biological Psychiatry Philadelphia, PA, November 5, 2013 – Childhood neglect and abuse, whether physical or psychological, confers a lifetime vulnerability to stress, anxiety, and mood problems. Such early-life stress is also suspected to contribute to the development of chronic pain in adulthood.

In fact, there is growing concern that chronic pain syndromes may be a complication of posttraumatic stress disorder (PTSD). However, this link is particularly challenging to study because many stressful events that produce PTSD also produce physical trauma. In addition, much of the research conducted in animals has not accurately reflected the early-life stress experienced by humans.

Inspired by a conversation with the violinist Itzhak Perlman, about students whose performance plateaued for unclear reasons, researchers led by Dr. Jon Levine at the University of California San Francisco, set out to rectify these gaps in understanding.

To do so, they used an animal model of maternal neglect that stresses rat mothers by restricting nesting/bedding material. These stressed rat mothers do not provide consistent levels of nurturing to their pups, i.e., the mothers are present but their care is unpredictable, resulting in increased levels of stress in the pups. The pups were otherwise not harmed or stressed.

Pups that had experienced this early-life stress showed increased reactivity to painful stimuli, particularly if they were exposed to a mild stress, an unpredictable unpleasant noise, as adults.

This enhanced muscle pain was related to both catecholamines, natural compounds in the body involved in the "fight-or-flight" response, and cytokines, molecules involved in the body's inflammatory response system. Interestingly, interventions that blocked the actions of the catecholamines and cytokines reduced the sensitivity to pain in the stressed pups.

"While it has been recognized for some time that early life events can shift homeostatic balance, predisposing adults to the development of chronic pain, that this could be mediated by a peripheral mechanism, involving the interaction between immune and neuroendocrine stress axes suggests novel approaches to detecting individuals at risk as well as to treatment of chronic pain," commented Levine.

This study suggests a 'two hit model' for the risk for pain syndromes: an initial stressor that predisposes to increased reactivity to later stress. The authors implicate both stress response and inflammation systems in the body in the link between stress and pain, potentially pointing to new treatment mechanisms.

"Chronic pain is a significant problem for people with PTSD. One reason for the co-occurrence of PTSD and pain is that the events that produce PTSD also may be associated with bodily harm. We have long known that childhood stress increases the vulnerability to PTSD. This new study also raises the possibility that early life stressors may increase the risk for pain syndromes," noted John H. Krystal, M.D., Editor of Biological Psychiatry.

### The article is "Stress in the Adult Rat Exacerbates Muscle Pain Induced by Early-Life Stress" by Pedro Alvarez, Paul G. Green, and Jon D. Levine (doi: 10.1016/j.biopsych.2013.04.006). The article appears in Biological Psychiatry, Volume 74, Issue 9 (November 1, 2013), published by Elsevier.

Notes for editors Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Jon D. Levine at +1 415 476 5108 or Jon.Levine@ucsf.edu.

The authors' affiliations, and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 4th out of 135 Psychiatry titles and 13th out of 251 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2012 Impact Factor score for Biological Psychiatry is 9.247.

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