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The Journal of Neuroscience, May 28, 2008, 28(22):5721-5730; doi:10.1523/JNEUROSCI.0256-08.2008

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Neurobiology of Disease
Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

Sachia G. Khasar,2,3 Jennifer Burkham,1,3 Olayinka A. Dina,2,3 Adrienne S. Brown,2,3 Oliver Bogen,2,3 Nicole Alessandri-Haber,2,3 Paul G. Green,2,3 David B. Reichling,2,3 and Jon D. Levine1,2,3

1Department of Medicine, Division of Rheumatology, 2Department of Oral and Maxillofacial Surgery, and 3Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440

Correspondence should be addressed to Dr. Jon D. Levine, Box 0440, C-522, University of California, San Francisco, San Francisco, CA 94143-0440. Email: jon.levine{at}ucsf.edu

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E2 or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (Gs to Gi), and for prostaglandin E2, emergence of novel dependence on protein kinase C{varepsilon}. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.

Key words: fibromyalgia; G-protein; hyperalgesia; protein kinase C{varepsilon}; catecholamine; glucocorticoid

Received Sept. 12, 2007; revised April 3, 2008; accepted April 20, 2008.

Correspondence should be addressed to Dr. Jon D. Levine, Box 0440, C-522, University of California, San Francisco, San Francisco, CA 94143-0440. Email: jon.levine{at}ucsf.edu






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