MODULATION OF KAPPA-OPIOID RECEPTOR-MEDIATED TOLERANCE IN THE GUINEA-PIG ILEUM BY CHRONIC COADMINISTRATION OF DIHYDROPYRIDINES

The influence of the L-type Ca2+ channel modulators nimodipine (a Ca2 blocker) and BAY K 8644 (a Ca2+ activator) on the expression of toler ance to the inhibitory effects of kappa- and mu-opioid agonists in the guinea-pig ileum from guinea-pigs rendered tolerant to the kappa-opio id receptor agonist U-50,488H was investigated. Tolerance to U-50,488H was induced by its administration (15 mg/kg twice a day) for 4 days. Control groups received saline at the same time schedule. Chronic infu sion of guinea-pigs with nimodipine (2 mu g/mu l/h for 7 days) or BAY K 8644 (0.5 mu g/mu l/h for 7 days), did not cause any modification of the height of contractions induced by electrical stimulation of the m yenteric plexus-longitudinal muscle (MPLM) preparation from naive guin ea-pigs. The Ca2+ antagonist nimodipine increases the potency of U-50, 488H (selective kappa agonist) to reduce the amplitude of neurogenic c ontractions of the MPLM strip in ndive animals, whereas the Ca2+ activ ator BAY K 8644 induced the opposite effect. However, the effect of DA MGO (selective mu agonist) was not modified in guinea-pigs infused wit h nimodipine or BAY K 8644. Tolerance to the inhibitory effects of bot h U-50,488H and DAMGO was observed following administration of U-50,48 8H for 4 days and was revealed as a rightward shift of the concentrati on-response curves for the two agonists. Chronic infusion of guinea-pi gs with nimodipine concurrently with chronic U-50,488H, markedly atten uated the expression of selective tolerance to U-50,488H as well as th e cross-tolerance between U-50,488H and DAMGO. By the contrary, the ma gnitude of tolerance to U-50,488H and to DAMGO was enhanced by concomi tant infusion of BAY K 8644. The results suggest that, in the GPI, kap pa-opioid receptor may be functionally linked to the dihydropyridine-s ensitive Ca2+ channel: The blockade of the channel increased whereas i ts activation reduced the potency of U-50,488H. In chronic experiments , nimodipine prevented the expression of tolerance to U-50,488H and th e cross-tolerance between U-50,488H and DAMGO, whereas BAY K 8644 prod uced the opposite effect. These results suggest that, in the GPI, sele ctive tolerance to kappa-agonist as well as cross-tolerance between ka ppa- and mu-opioid agonists would involve activation of L-type Ca2+ ch annels, which could indicate that intracellular Ca2+ may be the final common pathway through which myenteric neurons adapt to the chronic op ioid exposure.