Role of L-type Ca2+ channels in attenuated morphine antinociception in streptozotocin-diabetic rats.

The role of L-type Ca2+ channels in morphine antinociception was studied in streptozotocin-induced diabetic and control rats, using [3H]PN200-110 [isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycabonylpyridine-3-caboxylate] binding (0.005-1.0 nmol/l) and rat whole brain membranes, to determine if the attenuation of morphine antinociception was related to alterations in dihydropyridine-sensitive Ca2+ channel binding characteristics. The tail-flick antinociceptive effect of morphine (4 mg/kg, i.p.) was significantly reduced in diabetic rats in comparison to that in controls. Nimodipine (0.1-3 mg/kg, i.p.) did not produce antinociception but significantly potentiated the morphine response in control rats. Nimodipine (0.3-3 mg/kg, i.p.) reversed the attenuation of morphine antinociception in a dose-dependent manner in diabetic rats. Moreover, insulin (2 U/kg, s.c.) [correction of mu/kg] reversed the attenuated morphine antinociception in streptozotocin-diabetic rats. A significant increase in the Bmax (+41%) of [3H]PN200-110 binding was observed in diabetic rat brain membranes compared to that in control rats. However, there was no change in affinity (Kd) value of [3H]PN200-110. The reduced morphine response in diabetic rats, in accordance with up-regulation of dihydropyridine sites, may be due to an increased Ca2+ influx through L-type channels. These results suggest a functional role of L-type Ca2+ channels in morphine antinociception and the diabetic state may lead to alterations in their density.