Involvement of κ‐opioid receptors in visceral nociception in mice

Abstract

It has been shown that the behavioural responses to chemically evoked visceral nociception are increased in transgenic mice lacking the j-opioid receptor (KOR). The aim of the present study was to evaluate the contribution of KOR in mechanically evoked visceral pain by performing colorectal distension (CRD) and monitoring the subsequent visceromotor response (VMR) in control mice (KOR +/+ ) and in mice lacking KOR (KOR )/) ). Pseudo-affective visceral pain responses were evoked in conscious mice using increasing (10-80 mmHg) and repeated (12 · 55 mmHg) phasic CRD paradigms. The resulting VMR was determined by monitoring the electromyographic activity of the abdominal muscle. The increasing and repeated CRD paradigms, respectively, evoked similar responses in both KOR +/+ and KOR )/) mice. The selective KOR-agonists U-69593 (5 and 25 mg kg )1 , s.c.) and asimadoline (25 mg kg )1 , s.c.) significantly decreased the VMR in KOR +/+ mice, while having no effect in KOR )/) mice. In contrast, the selective l-opioid receptor agonist fentanyl significantly reduced the VMR in both types of mice and appeared more efficacious in KOR )/) mice. The opioid receptor antagonist naloxone (0.3-30 mg kg )1 s.c.) did not affect the response to CRD in C57BL/6 mice at any dose tested. In conclusion, the data confirm that the KOR agonists used in this study inhibit the VMR to CRD in mice by acting via KOR receptors. In addition, the data suggest that the endogenous opioid system is not likely to modulate the VMR to mechanically evoked visceral pain in mice.

Mu and delta opioid receptor knockout mice show increased colonic sensitivity

“…Here, we have shown an increase in visceromotor response to CRD in naïve MOR and DOR global KO mice, indicating that global activity at these two opioid receptors regulates basal visceral pain. A previous study has found a normal sensitivity to CRD in kappa opioid receptor KO mice (Larsson et al., ), and altogether this suggests that global MOR and DOR activities have major influences on the response to colon distension. In assays of visceral chemical nociception to intraperitoneal acetic acid, MOR KO mice showed diminished or normal writhing response (Sora et al., ; Weibel et al., ), DOR KO showed no phenotype (Filliol et al., ) and KOR KO mutants were more sensitive than wild‐type mice (Simonin et al., ).…”

“…Colitis models induced by either 2,4,6‐trinitrobenzene sulphonic acid (TNBS), adoptive transfer of CD4 + CD45RB high T lymphocytes or dextran sodium sulphate (DSS) have shown that endogenous mu opioid activity dampened inflammation (Philippe et al., ; Goldsmith et al., ; Sobczak et al., ; Anselmi et al., ), and the expression of MOR (Pol et al., ) and DOR (Pol et al., ) was increased during intestinal inflammation in mice. Although KOR activation produced visceral anti‐hyperalgesia (Sengupta et al., ; Sobczak et al., ; Mosinska et al., ), a comparable sensitivity to CRD was found in KOR knockout (KO) and wild‐type (WT) mice (Larsson et al., ) suggesting no major implication of the endogenous KOR tone. However, the contribution of endogenous MOR and DOR activities on visceromotor responses to colorectal distension (CRD) under basal (naïve) and acute inflammatory conditions is still unknown.…”

Analgesic Efficacy of Peripheral κ-Opioid Receptor Agonist CR665 Compared to Oxycodone in a Multi-modal, Multi-tissue Experimental Human Pain Model

“…42 ) and/or low affinity for the -opioid receptor (e.g., Allescher et al 43 ). These clinical reports, together with physiologic evidence for a role of -opioid receptors in modulating visceral pain, 44,45 have lead to an intensified search for high-affinity, peripherally selective -opioids.…”

Drug Management of Visceral Pain: Concepts from Basic Research

“…There is evidence that fentanyl significantly reduces visceromotor responses to a greater extent when kappa receptors are nonfunctional (kappa receptor gene “knocked-out” mice) [148]. The combination of fentanyl and the kappa receptor agonist spiradoline produced dose-dependent supra-additive antinociception in an animal model involving colorectal distention.…”