Corticosterone mediates reciprocal changes in CB 1 and TRPV1 receptors in primary sensory neurons in the chronically stressed rat.
OBJECTIVE
Chronic stress is associated with visceral hyperalgesia in functional gastrointestinal disorders. We investigated whether corticosterone plays a role in chronic psychological stress-induced visceral hyperalgesia.


METHODS
Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous corticosterone injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486 and cannabinoid-receptor agonist WIN55,212-2. The visceromotor response to colorectal distension was measured. Receptor protein levels were measured and whole-cell patch-clamp recordings were used to assess transient receptor potential vanilloid type 1 (TRPV1) currents in L6-S2 dorsal root ganglion (DRG) neurons. Mass spectrometry was used to measure endocannabinoid anandamide content.


RESULTS
Chronic WA stress was associated with visceral hyperalgesia in response to colorectal distension, increased stool output and reciprocal changes in cannabinoid receptor 1 (CB1) (decreased) and TRPV1 (increased) receptor expression and function. Treatment of WA stressed rats with RU-486 prevented these changes. Control rats treated with serial injections of corticosterone in situ showed a significant increase in serum corticosterone associated with visceral hyperalgesia, enhanced anandamide content, increased TRPV1, and decreased CB1 receptor protein levels, which were prevented by co-treatment with RU-486. Exposure of isolated control L6-S2 DRGs in vitro to corticosterone reproduced the changes in CB1 and TRPV1 receptors observed in situ, which was prevented by co-treatment with RU-486 or WIN55,212-2.


CONCLUSIONS
These results support a novel role for corticosterone to modulate CB1 and TRPV1-receptor pathways in L6-S2 DRGs in the chronic WA stressed rat, which contributes to visceral hyperalgesia observed in this model.
Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, MSRB III, Room 9315, Ann Arbor, Michigan 48109, USA. hongss@med.umich.edu
Shuangsong
S
Hong
Gen
G
Zheng
Xiaoyin
X
Wu
Natasha T
NT
Snider
Chung
C
Owyang
John W
JW
Wiley
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002908:Chronic Disease; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D005243:Feces; D005727:Ganglia, Spinal / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D011984:Sensory Receptor Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000032:analysis / Q000378:metabolism*
D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D011965:Receptors, Glucocorticoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D015735:Mifepristone; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D003345:Corticosterone