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  • Title: Ca2+ channel blocker, diltiazem, prevents physical dependence and the enhancement of protein kinase C activity by opioid infusion in rats.
    Author: Tokuyama S, Feng Y, Wakabayashi H, Ho IK.
    Journal: Eur J Pharmacol; 1995 Jun 06; 279(1):93-8. PubMed ID: 7556388.
    Abstract:
    The influence of an L-type Ca2+ channel blocker, diltiazem [(2S-cis)-3-(acetyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2- (4- methoxyphenyl)-1,5-benzothiazepin-4(5H)-one], on the behavioral signs of naloxone (opioid receptor antagonist)-precipitated withdrawal syndrome and the enhancement of protein kinase C activity in the pons/medulla regions of rats rendered dependent on morphine (mu-opioid receptor agonist) or butorphanol (mu/delta/kappa mixed opioid receptor agonist) was investigated. The expression of physical dependence produced by continuous intracerebroventricular (i.c.v.) infusion of morphine (26 nmol/microliters per h) or butorphanol (26 nmol/microliters per h) for 3 days, as evaluated by naloxone (5 mg/kg, i.p.)-precipitated withdrawal signs, was dose dependently attenuated by concomitant infusion of diltiazem (10 and 100 nmol/microliters per h). Furthermore, diltiazem (100 nmol/microliters per h) completely inhibited the enhancement of cytosolic protein kinase C activity in the pons/medulla regions in rats rendered dependent by continuous infusion with morphine or butorphanol. These results suggest that the augmentation of intracellular Ca2+ concentration mediated through L-type Ca2+ channels during continuous opioid infusion leads to the enhancement of cytosolic protein kinase C activity in the pons/medulla region which is intimately involved in the development and/or expression of physical dependence on opioids.
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