dihydropyridines and Morphine-Dependence

The effect of chronic administration of dihydropyridine calcium channel antagonist nimodipine (1 mg/kg/day) given concurrently with morphine on the signs of morphine withdrawal and on the [3H]nitrendipine binding in the rat brain has been investigated. Chronic morphine administration in increasing daily doses from 20 mg/kg to 70 mg/kg for 24 days and consequent withdrawal for 24 h induced loss of body weight, wet dog shakes, episodes of writhing and yawning behaviour. The density of [3H]nitrendipine binding was elevated in the cortex and limbic structures but not in the striatum after chronic morphine treatment. Chronic concurrent administration of nimodipine prevented the loss of body weight and reduced the scores of wet dog shakes and writhing, but did not affect yawning behaviour at 24 h after morphine withdrawal. The concurrent nimodipine treatment also prevented the rise in the density of central dihydropyridine binding sites which occurred upon chronic morphine treatment. These results suggest that chronic nimodipine treatment attenuates the development of the withdrawal signs which occur upon the termination of chronic morphine treatment by preventing the up-regulation of the central dihydropyridine-sensitive binding sites.

Topics: Animals; Brain; Dihydropyridines; Male; Morphine; Morphine Dependence; Motor Activity; Nimodipine; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The density of cortical [3H]nitrendipine binding sites was elevated by over 40% in rats rendered morphine-abstinent by administration of naloxone after chronic treatment with morphine. The morphine-abstinent rats had significantly shortened response latencies in the hot-plate test. Nifedipine treatment abolished the signs of abstinence and normalized the hot-plate latencies in morphine-dependent, naloxone-treated rats. The results indicate that the symptoms of abstinence are related to a functional state of cortical dihydropyridine-sensitive calcium channels.

Topics: Animals; Behavior, Animal; Brain Chemistry; Calcium Channel Blockers; Calcium Channels; Cerebral Cortex; Dihydropyridines; Hippocampus; Male; Morphine Dependence; Naloxone; Nifedipine; Nitrendipine; Pain Measurement; Rats; Rats, Inbred Strains; Receptors, Nicotinic; Substance Withdrawal Syndrome

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.

Topics: Analgesics; Animals; Behavior, Animal; Brain; Calcium Channels; Dihydropyridines; Male; Mice; Morphine; Morphine Dependence; Myocardium; Naloxone; Nimodipine; Rats; Rats, Inbred Strains; Receptors, Nicotinic; Substance Withdrawal Syndrome