Cross-tolerance between kappa and mu opioid agonists in the guinea pig ileum myenteric plexus

Abstract

The aim of the present investigation was to determine whether chronic activation of kappa opioid receptor induces development of tolerance of kappa (specific tolerance) and to mu (cross-tolerance) agonists in the guinea pig ileum myenteric plexus-longitudinal muscle strip. trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidynyl)ciclohexyl]-benzeneacetamide (U-50,488H) a selective kappa agonist, morphine (prototype of a mu agonist) and DAMGO (a selective mu agonist) were chosen. Tolerance to the kappa agonist was induced by chronic administration of the kappa agonist (15 mg/kg i.p. twice a day for 4 days). The guinea pigs were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve. In addition, we observed a decrease in the maximum response and in the slope. Preparations from chronically U-50,488H-treated guinea pigs were also tolerant to the inhibitory effects of both the mu-selective agonist DAMGO and morphine. That is, there was cross-tolerance to the mu agonists. The development of tolerance to DAMGO and morphine was characterized by a rightward shift of the concentration-response curve, a decrease in maximum response and a decrease in the slope, although the degree of tolerance appeared to be less than that observed to U-50,488H. These data suggest that tolerance at the myenteric plexus level may be associated with a functional change in the myenteric neurons that is unrelated to the individual receptor system.