Ca2+ channel blocker, diltiazem, prevents physical dependence and the enhancement of protein kinase C activity by opioid infusion in rats.
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.
Tokuyama
S
S
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216, USA.
Feng
Y
Y
Wakabayashi
H
H
Ho
I K
IK
D000818:Animals; D002077:Butorphanol / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000201:enzymology; D009021:Morphine Dependence / Q000517:prevention & control; D009270:Naloxone / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000517:prevention & control*; D011149:Pons / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D002121:Calcium Channel Blockers; D009270:Naloxone; D011493:Protein Kinase C; D004110:Diltiazem; D002077:Butorphanol