Prolonged morphine treatment increases rat brain dihydropyridine binding sites: possible involvement in development of morphine dependence.

Regulation of L-type Ca2+ channels by morphine in rat brain was determined by the binding of [3H]nimodipine. Morphine, administered by subcutaneous pellet implantation, increased the density of [3H]nimodipine binding sites in a time- and dose-dependent manner and this effect was reversible upon removal of the pellets. Increases in these dihydropyridine sites were localized to the cortex, hippocampus, hypothalamus and brainstem but not to the cerebellum and striatum. Additional experiments were performed to test the ability of different Ca2+ channel antagonists to affect naloxone-precipitated withdrawal in morphine-dependent mice and rats. These drugs effectively reduced the incidence of naloxone-induced jumping in mice and several of the withdrawal signs in rats. Taken together, our study underscores the plasticity of brain L-type Ca2+ channels and suggests that their upregulation might contribute to morphine dependence.