Calcium channel inhibitors suppress the morphine-withdrawal syndrome in rats.

Abstract

The effects of the Ca2+-channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg-1)-induced abstinence syndrome in morphine-dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured, using high performance liquid chromatography and electrochemical detection or gas chromatography-mass spectrometry, in various brain regions of these animals. Possible interactions of nimodipine and verapamil with opioid receptors were evaluated by examining their ability to displace [3H]-naloxone binding to brain membranes. Verapamil (5, 10 and 50 mg kg-1) and nimodipine (1, 5 and 10 mg kg-1) dose-dependently reduced most of the signs of morphine abstinence. Naloxone-precipitated abstinence decreased the NA content in the cortex, hippocampus, brainstem and cerebellum. In the same brain regions the content of MHPG increased, suggesting an increased release of the amine during morphine abstinence. Nimodipine (10 mg kg-1 i.v.) did not change the content of NA or MHPG in the cortex, hippocampus and brainstem. However, nimodipine pre-treatment markedly reduced the changes in NA and MHPG content induced by the abstinence syndrome. Neither verapamil nor nimodipine displaced [3H]-naloxone from its binding sites. These results suggest that Ca2+-channel blockers suppress the behavioural and neurochemical expressions of morphine abstinence by a mechanism that differs from those of opioids or alpha 2-adrenoceptor agonists.