Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain.
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 E(2) 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 (G(s) to G(i)), and for prostaglandin E(2), emergence of novel dependence on protein kinase C epsilon. 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.
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 94143-0440, USA.
Sachia G
SG
Khasar
Jennifer
J
Burkham
Olayinka A
OA
Dina
Adrienne S
AS
Brown
Oliver
O
Bogen
Nicole
N
Alessandri-Haber
Paul G
PG
Green
David B
DB
Reichling
Jon D
JD
Levine
D000315:Adrenalectomy / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000494:pharmacology; D015232:Dinoprostone; D004195:Disease Models, Animal; D004837:Epinephrine / Q000009:adverse effects / Q000097:blood; D006727:Hormone Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000294:innervation; D009475:Neurons, Afferent / Q000502:physiology*; D010146:Pain / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000294:innervation; D013016:Sound / Q000009:adverse effects; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology*; D013997:Time Factors
D006727:Hormone Antagonists; D015735:Mifepristone; D015232:Dinoprostone; D003345:Corticosterone; D004837:Epinephrine