EFFECT OF CHRONIC ADMINISTRATION OF DIHYDROPYRIDINE CA2-INDUCED TOLERANCE TO MU-OPIOID AND KAPPA-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS( CHANNEL LIGANDS ON SUFENTANIL)

The present investigation was aimed at elucidating if the entry of Ca2 + plays a role in the development of tolerance to mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus. For this purpose, the influence of the L-type Ca2+ channel modulators nimodipine (Ca2+ b locker) and Bay K 8644 (Ca2+ activator) on the expression of tolerance to the inhibitory effects of mu- and kappa-opioid agonists in the ile um of guinea pigs rendered tolerant to sufentanil was investigated. Ch ronic perfusion of guinea pigs with nimodipine (2 mu g/mu l/h for 7 da ys) or Bay K 8644 (0.5 mu g/mu l/h for 7 days) did not cause any modif ication of the height of contractions induced by electrical stimulatio n of the myenteric plexus-longitudinal muscle (MPLM) strip from naive animals. Tolerance to sufentanil (a selective mu-agonist) was induced by s.c. implantation of osmotic minipumps for 7 days, which deliver at 2 mu g/mu l/h. Control groups received saline. Tolerance to sufentani l as well as to U-50,488H (selective kappa-agonist) was observed follo wing chronic treatment with sufentanil and was revealed as a rightward shift of the concentration-response curves. Chronic perfusion of guin ea pigs with the Ca2+ antagonist nimodipine concurrently with chronic sufentanil, markedly blocked the expression of tolerance to sufentanil , as well as the cross-tolerance between sufentanil and U-50,488H. On the contrary, when guinea pigs were perfused with the Ca2+ agonist Bay K 8644 concurrently with sufentanil, it enhanced the magnitude of tol erance to both sufentanil and U-50,488H. These results suggest that, i n guinea pig ileum, chronic exposure to opioids may involve the activa tion of L-type Ca2+ channel, which would indicate that intracellular C a2+ may be one of the final pathways through which myenteric neurons a dapt to the chronic opioid exposure.