Effect of chronic administration of dihydropyridine Ca²⁺ channel ligands on sufentanil-induced tolerance to μ- and κ-opioid agonists in the guinea pig ileum myenteric plexus

Abstract

The present investigation was aimed at elucidating if the entry of Ca²⁺ plays a role in the development of tolerance to μ- and κ-opioid agonists in the guinea pig ileum myenteric plexus. For this purpose, the influence of the L-type Ca²⁺ channel modulators nimodipine (Ca²⁺ blocker) and Bay K 8644 (Ca²⁺ activator) on the expression of tolerance to the inhibitory effects of μ- and κ-opioid agonists in the ileum of guinea pigs rendered tolerant to sufentanil was investigated. Chronic perfusion of guinea pigs with nimodipine (2 μg/μl/h for 7 days) or Bay K 8644 (0.5 μg/μl/h for 7 days) did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) strip from naive animals. Tolerance to sufentanil (a selective μ-agonist) was induced by s.c. implantation of osmotic minipumps for 7 days, which deliver at 2 μg/μl/h. Control groups received saline. Tolerance to sufentanil as well as to U-50,488H (selective κ-agonist) was observed following chronic treatment with sufentanil and was revealed as a rightward shift of the concentration-response curves. Chronic perfusion of guinea 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 tolerance to both sufentanil and U-50,488H. These results suggest that, in guinea pig ileum, chronic exposure to opioids may involve the activation of L-type Ca²⁺ channel, which would indicate that intracellular Ca²⁺ may be one of the final pathways through which myenteric neurons adapt to the chronic opioid exposure.