Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat.
The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release.
Friedrich
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Department of Pharmacology, University of Iowa College of Medicine, Bowen Science Building, Iowa City, Iowa, USA. ann-friedrich@uiowa.edu
Gebhart
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GF
D000700:Analgesics / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D003092:Colitis / Q000473:pathology; D003106:Colon / Q000187:drug effects; D020109:Devazepide / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011377:Proglumide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012007:Rectum / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014781:Viscera / Q000187:drug effects*
D000700:Analgesics; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D009020:Morphine; D014302:Trinitrobenzenesulfonic Acid; D011377:Proglumide; D020109:Devazepide