Calcium channel inhibitors suppress the morphine‐withdrawal syndrome in rats

Abstract

1 The effects of the Ca2"-channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg-')-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 ofthese animals. Possible interactions of nimodipine and verapamil with opioid receptors were evaluated by examining their ability to displace [3HJ-naloxone binding to brain membranes.2 Verapamil (5, 10 and 50mg kg-')and nimodipine (1, 5and 10mg kg-') dose-dependently reduced most of the signs of morphine abstinence. 3 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. 4 Nimodipine (10mgkg-' 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.5 Neither verapamil nor nimodipine displaced [3H]-naloxone from its binding sites.6 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 a2-adrenoceptor agonists.

Different Mechanisms Mediate Development and Expression of Tolerance and Dependence for Peripheral μ-Opioid Antinociception in Rat

“…Our results agree with the finding that chronic administration of calcium channel blockers can attenuate the expression of opioid tolerance in the C NS (Bongianni et al, 1986;Ruiz et al, 1993;Berstein and Welch, 1995;Diar et al, 1995;Diaz et al, 1995;Garaulet et al, 1996). Although the mechanism by which calcium is involved in expression of tolerance and dependence is uncertain, activation of PKC may influence neurons by changing conductances of ion channels (Alkon et al, 1986), including those for calcium.…”

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs

“…They also decreased the severity of the opiate withdrawal syndrome (Bongianni et al, 1986). They were considerably less effective against other types of seizures ) and appear to be relatively selective for drug withdrawal.…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…The adverse motivational state associated with withdrawal can promote renewed drug intake (Koob, 2009;Koob and Volkow, 2010), and agents that reduce these effects could be useful therapeutically in human addicts. Thus, LCBBs reduce withdrawal signs related to morphine (Bongianni et al, 1986;Baeyens et al, 1987;Ramkumar and el-Fakahany, 1988;Antkiewicz-Michaluk et al, 1990;Esmaeili-Mahani et al, 2008), nicotine (Jackson and Damaj, 2009), and ethanol (Bone et al, 1989;Watson and Little, 2002). LCCBs had no general anticonvulsant action against bicuculline-or pentylenetetrazol-induced seizures (Watson and Little, 2002), suggesting a more specific impact on drug-related physical signs rather than a more general effect on seizures and convulsions.…”