Opioid tolerance and supersensitivity induce regional changes in the autoradiographic density of dihydropyridine-sensitive calcium channels in the rat central nervous system.

ABSTRACT

Chronic opioid administration induces adaptations in neurones resulting in opioid tolerance and dependence. The changes in dihydropyridine (DHP)-sensitive Ca(2+) channels (L-type) associated with tolerance and supersensitivity to the antinociceptive effect of the micro-opioid receptor agonist sufentanil were analyzed in the central nervous system (CNS) of rats. Autoradiographic assays were performed with [(3)H]PN-200-110 (isopropyl 4-(2,1, 3-benzoxadiazol-4-yl)-1,4-dihydro-2, 6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate). Chronic s.c. infusion of sufentanil (2 microg/h) for 7 days, which has been shown to induce tolerance to the opioid antinociceptive effect, produced an up-regulation of DHP binding sites. The highest increases in density were localized in regions involved in nociceptive transmission and perception, such as the dorsal horn of the spinal cord, the dorsal raphe nucleus, the central grey matter, the thalamic nuclei, and the somatosensory cortex. Animals were rendered supersensitive to the antinociceptive effect of sufentanil by chronic and simultaneous infusion of sufentanil (2 microg/h) and nimodipine (1 microg/h) for 7 days. Under these conditions, a greater increase in the number of DHP binding sites was observed in the spinal cord, central grey matter, dorsal raphe nucleus, and somatosensory neocortex, when compared to the sufentanil group. The role of an increased influx through L-type channels in opioid tolerance is reinforced, whereas their persistent blockade is essential for the expression of opioid supersensitivity.