Effects of kappa opioids in the inflamed rat colon

Abstract

The objective of this study was to examine the antinociceptive effects of peripherally restricted κ-opioid receptor agonists (ORAs) in a rat model of inflammatory bowel disease produced by intracolonic instillation of trinitrobenzine sulfonic acid (TNBS). Antinociceptive effects of μ-(morphine) and κ-ORAs (EMD 61 753 and ICI 204 488) were evaluated in a behavioral model of visceral nociception. The effects of these agonists and a δ-ORA (SNC 80) on responses of pelvic nerve afferent fibers innervating the colon were also tested. In the behavioral study, systemic injections of morphine and both κ-ORAs dose-dependently inhibited the visceromotor response to colorectal distension in rats with uninflamed or inflamed colons. The inhibitory effects of κ-ORAs, but not morphine, were significantly greater in rats with colons inflamed 4 days previously by TNBS. A μ-receptor-selective dose (30 μg/kg) of naloxone methiodide (NLXM) blocked the inhibitory effect of morphine, but not of EMD 61 753. In the single-fiber study, neither morphine nor the δ-ORA SNC 80 attenuated the responses of pelvic nerve afferent fibers, whereas κ-ORAs dose-dependently inhibited responses of pelvic nerve afferent fibers with significantly greater potency in the inflamed colon. Pretreatment with a non-opioid receptor-selective dose (2 mg/kg) of NLXM produced a rightward shift in the dose-response function of EMD 61 753. The greater potency of κ-ORAs in the TNBS-inflamed condition suggests a peripheral upregulation of κ-opioid receptors in colonic inflammation.