REGULATION OF DIHYDROPYRIDINE-SENSITIVE CA++ OPIOID TOLERANCE AND SUPERSENSITIVITY IN RATS

The changes in cerebral dihydropyridine (DHP)-sensitive Ca++ channels (L-type) associated with tolerance and supersensitivity to the antinoc iceptive effect of the mu-opioid receptor agonist sufentanil were anal yzed in rats. The tail-flick test was used to asses the nociceptive th reshold. DHP binding and autoradiographic assays were performed with [ H-3]nimodipine and [H-3]PN 200-110 [isopropyl dimethyl-5-methoxycarbon ylpyridine-3-carboxylate], respectively. Chronic s.c. infusion of sufe ntanil (2 mu g/hr) for 7 days induced tolerance (tolerance index, 5.6) in association with up-regulation of DHP binding sites in cerebral co rtex membranes (+36%), as well as in brain sections. Animals were rend ered hypersensitive to the antinociceptive effect of sufentanil by chr onic and simultaneous infusion of sufentanil (2 mu g/hr) and nimodipin e (1 mu g/hr) for 7 days (potentiation index, 40 vs. tolerant). Under these conditions, a greater increase in the number of DHP binding site s was observed in cortex membranes (+71%), and more evidently in brain sections. In these animals, withdrawal of nimodipine for 48 hr return ed the dose-response curve of sufentanil to the tolerant values, where as Ca++ channels remained increased. The role of an increased influx t hrough L-type channels in opioid tolerance is reinforced. Our results also suggest that, although changes in neuronal Ca++ fluxes are not th e only underlying mechanism, the increase and the sustained blockade o f Ca++ channels with nimodipine is essential for the expression of opi oid supersensitivity.