title: Chronic stress and peripheral pain: Evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways.
abstract: Chronic stress alters the hypothalamic-pituitary-adrenal (HPA) axis and enhances visceral and somatosensory pain perception. It is unresolved whether chronic stress has distinct effects on visceral and somatosensory pain regulatory pathways. Previous studies reported that stress-induced visceral hyperalgesia is associated with reciprocal alterations of endovanilloid and endocannabinoid pain pathways in DRG neurons innervating the pelvic viscera. In this study, we compared somatosensory and visceral hyperalgesia with respect to differential responses of peripheral pain regulatory pathways in a rat model of chronic, intermittent stress. We found that chronic stress induced reciprocal changes in the endocannabinoid 2-AG (increased) and endocannabinoid degradation enzymes COX-2 and FAAH (decreased), associated with down-regulation of CB1 and up-regulation of TRPV1 receptors in L6-S2 DRG but not L4-L5 DRG neurons. In contrast, sodium channels Nav1.7 and Nav1.8 were up-regulated in L4-L5 but not L6-S2 DRGs in stressed rats, which was reproduced in control DRGs treated with corticosterone in vitro. The reciprocal changes of CB1, TRPV1 and sodium channels were cell-specific and observed in the sub-population of nociceptive neurons. Behavioral assessment showed that visceral hyperalgesia persisted, whereas somatosensory hyperalgesia and enhanced expression of Nav1.7 and Nav1.8 sodium channels in L4-L5 DRGs normalized 3 days after completion of the stress phase. These data indicate that chronic stress induces visceral and somatosensory hyperalgesia that involves differential changes in endovanilloid and endocannabinoid pathways, and sodium channels in DRGs innervating the pelvic viscera and lower extremities. These results suggest that chronic stress-induced visceral and lower extremity somatosensory hyperalgesia can be treated selectively at different levels of the spinal cord.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Gen
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: hongss@med.umich.edu.
authors.forename: Shuangsong
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hayes
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Wiley
mesh_terms: D000344:Afferent Pathways / Q000503:physiopathology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D019054:Evoked Potentials, Motor / Q000502:physiology; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005989:Glycerides / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology*; D007420:Intestine, Large / Q000294:innervation; D008297:Male; D009437:Neuralgia / Q000150:complications / Q000209:etiology / Q000473:pathology; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013315:Stress, Psychological / Q000097:blood / Q000150:complications*; D050916:TRPV Cation Channels / Q000378:metabolism; D059265:Visceral Pain / Q000209:etiology / Q000378:metabolism / Q000473:pathology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; D003345:Corticosterone
keywords: CB1; Chronic stress; Endocannabinoid; Pain; Sodium channel; Somatosensory hyperalgesia; Trpv1; Visceral hyperalgesia