Replicating Stress-Induced Analgesia May Hold Promise For Patients With Intractable Pain

Recent statistics indicate that one in five people worldwide suffer from moderate to severe chronic pain and that one in three are unable or less able to maintain an independent lifestyle due to their pain. The trauma of battle, attack by a predator, and even everyday stress often reduce the perception of pain. This phenomenon, called stress-induced analgesia (SIA), was first recognized by researchers after World War II. Little is known about the brain mechanisms responsible for SIA (i.e. the pain relief seen in response to stress). Research into the brain function underlying SIA may help identify novel clinical treatments for severe pain, by targeting these brain pathways.

Researchers at Oregon Health & Science University studied the role of the amygdala in SIA, utilizing an animal model to help identify mechanisms of pain relief. The amygdala or "almond" is a tiny cluster of neurons deep within the limbic or emotional centers of the forebrain. The amygdala is involved in fear and stress responses, and also has strong connections to the brain's principal pain modulation pathway, located in the brainstem.

The results of this study, A Candidate Neural Circuit for Stress-Induced Analgesia, will be presented by Nathan R. Selden, MD, PhD, FACS, 2:57 to 3:09 p.m. on Tuesday, April 17, 2007, during the 75th Annual Meeting of the American Association of Neurological Surgeons in Washington, D.C. Co-authors are Justin Ortiz, MD, Liesl Close, BA, and Mary M. Heinricher, PhD.

Researchers tested the hypothesis that stress-induced release of noradrenaline into the central nucleus of the amygdala (CeA) mediates SIA, by microinjecting precise doses of the a2-adrenergic agonist, clonidine into lightly anesthetized adult male Taconic rats, according to an Institutional Animal Care and Use Committee (IACUC)-approved protocol. Clonidine mimics the brain's stress neurotransmitter, norepinephrine. Following injection, the rats were monitored to analyze the effect of the injection on thermal pain perception. Tail-flick withdrawal latencies (TFL) to noxious heat were used to evaluate pain perception. The following results were noted:

-- Microinjection of clonidine bilaterally into the CeA produced a dose-dependent increase in the TFL (i.e. analgesia, or pain relief) as compared to saline vehicle alone, which showed no change from baseline.

-- Low, medium, and high doses of clonidine led to an increase in TFL (i.e. analgesia) of 16 percent, 24 percent, and 47 percent over baseline respectively.

-- The analgesic effect was blocked by microinjection of the a2-adrenergic antagonist idazoxan into the CeA prior to clonidine, or by intraperitoneal injection of the a2-adrenergic antagonist, yohimbine, prior to clonidine.

-- The analgesia was not present if the injections were moved fractions of a millimeter to other nearby brain nuclei.

"The results of our research suggest that it is possible to pharmacologically mimic stress-induced analgesia, and should enable us to more precisely delineate the possible neurophysiological mechanisms of this natural phenomenon," said Dr. Selden.

"We are doing ongoing research aimed at blocking the analgesia caused by mildly unpleasant restraint stress in rats, using the same norepinephrine blockers tested in our initial experiments. The ultimate goal of this research is to identify therapeutic targets for the treatment of pain in patients, using non-opioid drugs, by taking advantage of the natural analgesia system normally activated in times of stress," concluded Dr. Selden.

Founded in 1931 as the Harvey Cushing Society, the American Association of Neurological Surgeons (AANS) is a scientific and educational association with more than 6,800 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public. All active members of the AANS are certified by the American Board of Neurological Surgery, the Royal College of Physicians and Surgeons (Neurosurgery) of Canada or the Mexican Council of Neurological Surgery, AC. Neurological surgery is the medical specialty concerned with the prevention, diagnosis, treatment and rehabilitation of disorders that affect the entire nervous system, including the spinal column, spinal cord, brain and peripheral nerves.

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