Effects of kappa-opioid receptor agonists on responses to colorectal distension in rats with and without acute colonic inflammation.
The objective of this study was to evaluate the effects of kappa-opioid receptor agonists on pressor and visceromotor responses to colorectal distension in awake, unrestrained rats, a model of visceral pain. Because visceral pain can be enhanced in the presence of inflammation, the study was conducted in rats that had been given either intracolonic saline or 5% acetic acid 6 hr before drug administration. We developed a method of staircase colorectal distension as a means of obtaining stimulus-response functions over a short period of time. Kappa-opioid receptor agonists, given i.v. in a cumulative dose paradigm, dose-dependently attenuated both the pressor and visceromotor responses to colorectal distension. In addition, all drugs tested also increased response threshold. The rank order of potency of the drugs tested was: CI977 > U69,593 > U50,488 > or = morphine > or = EMD61,753 > ICI204,448. Effective doses of these drugs were antagonized by naloxone, but not by either of two kappa-opioid receptor-selective antagonists (nor-binaltorphimine and 2-(3,4-dichlorophenyl)-N-methyl-N-(1-[3-isothiocyanate phenyl]-2-[1-pyrrolidinyl]ethyl)-acetamide). Acute inflammation of the colon did not lead to changes in the potency of the agonists tested. The present results provide further evidence that kappa-opioid receptor agonists significantly attenuate visceral nociception and, in conjunction with other information, suggest that a peripherally restricted kappa-opioid receptor agonist would be therapeutically effective in relieving visceral pain.
Burton
M B
MB
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, USA.
Gebhart
G F
GF
D000208:Acute Disease; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003092:Colitis / Q000503:physiopathology*; D003106:Colon / Q000503:physiopathology; D004576:Electromyography; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012007:Rectum / Q000503:physiopathology
D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa; D009270:Naloxone