Regulation of dihydropyridine-sensitive Ca++ channels during opioid tolerance and supersensitivity in rats.
The changes in cerebral dihydropyridine (DHP)-sensitive Ca++ channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the mu-opioid receptor agonist sufentanil were analyzed in rats. The tail-flick test was used to assess the nociceptive threshold. DHP binding and autoradiographic assays were performed with [3H]nimodipine and [3H]PN 200-110 [isopropyl 4-(2,1,3-benzoxadizol-4-yl)- 1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate], respectively. Chronic s.c. infusion of sufentanil (2 micrograms/hr) for 7 days induced tolerance (tolerance index, 5.6) in association with up-regulation of DHP binding sites in cerebral cortex membranes (+36%), as well as in brain sections. Animals were rendered hypersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 micrograms/hr) and nimodipine (1 microgram/hr) for 7 days (potentiation index, 40 vs. tolerant). Under these conditions, a greater increase in the number of DHP binding sites was observed in cortex membranes (+71%), and more evidently in brain sections. In these animals, withdrawal of nimodipine for 48 hr returned the dose-response curve of sufentanil to the tolerant values, whereas Ca++ channels remained increased. The role of an increased influx through L-type channels in opioid tolerance is reinforced. Our results also suggest that, although changes in neuronal Ca++ fluxes are not the only underlying mechanism, the increase and the sustained blockade of Ca++ channels with nimodipine is essential for the expression of opioid supersensitivity.
Díaz
A
A
Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
Ruíz
F
F
Flórez
J
J
Pazos
A
A
Hurlé
M A
MA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004357:Drug Synergism; D004361:Drug Tolerance; D017136:Ion Transport; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017409:Sufentanil / Q000494:pharmacology*
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009553:Nimodipine; C038806:1,4-dihydropyridine; D017409:Sufentanil; D002118:Calcium