CROSS-TOLERANCE BETWEEN MU-OPIOID AND KAPPA-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS

The present investigation was aimed at elucidating if chronic activati on of mu opioid receptor induces development of tolerance to mu (speci fic tolerance) and kappa agonists (cross-tolerance) in the guinea pig ileum myenteric plexus-longitudinal muscle strip. Morphine (prototype of mv agonist), [D-Ala(2), N-MePhe(4), Gly-ol(5)]enkephalin (DAMGO) an d sufentanil (selective mu-agonists) and U-50,488H (selective kappa ag onist) were selected. Tolerance to morphine was induced by subcutaneou s implantation of morphine pellets (75 mg per pellet) for 7 days. Tole rance to sufentanil was induced by subcutaneous implantation of osmoti c minipumps for 7 days, which deliver at a rate of 2 mu g/mu l/hr. Con trol groups received placebo pellets or minipumps of vehicle. Toleranc e to morphine and DAMGO was observed after chronic treatment with morp hine or sufentanil and was revealed as a rightward shift of the concen tration-response curve. In addition, a decrease in maximal response wa s observed. Preparations from morphine-pelleted guinea pigs were also tolerant to the kappa-selective agonist trans-(+/-)3,4-dichloro-N-meth yl-N-[2-(1 -pyrrolidynyl)-cyclohexyl]benzeneacetamide (U-50,488H); tha t is, there was cross-tolerance to the kappa agonist. The development of tolerance to U-50,488H was characterized by a parallel rightward sh ift of the concentration-response curve, but the maximal response was unchanged. Sufentanil-tolerant tissues were also tolerant to the inhib itory effects of U-50,488H (cross-tolerance). These data indicate that alterations occur during chronic mu opioid administration that are no t receptor specific and suggest that tolerance would be associated wit h a functional change in the myenteric neurons that is unrelated to in dividual receptor system.