title: The effect of nimodipine on opioid antagonist-induced upregulation and supersensitivity.
abstract: Regulation of calcium flux has been suggested to play a role in acute and chronic effects of opioids. Previous studies have shown calcium channel blockers can inhibit opioid agonist-induced downregulation of mu-opioid receptors and may reduce the magnitude of tolerance. In the present study, we determined if calcium channel blockade would affect increases in opioid receptor density and functional supersensitivity produced by chronic opioid antagonist treatment in the mouse. Mice were implanted subcutaneously with a 15-mg naltrexone (NTX) or placebo pellet. Mice also were implanted with an osmotic minipump that infused nimodipine (100 microg/kg/day) or a second placebo pellet. This protocol yielded four groups: nimodipine-NTX; nimodipine-placebo; placebo-NTX; placebo-placebo. On the seventh day, pumps and pellets were removed. Twenty-four hours later, a morphine dose-response study was conducted (tail flick); or mice were sacrificed and saturation binding studies ([3H]DAMGO) were performed in whole brain. NTX treatment significantly increased the analgesic potency of morphine by approximately 60%. Nimodipine increased the potency of morphine by approximately 50%. For mice treated with both nimodipine and NTX, there was an additive effect on morphine potency ( approximately 120% increase). In binding studies, NTX increased the density of mu-opioid receptors similarly ( approximately 60-70%) in the presence and absence of nimodipine treatment, with no change in affinity. No effect of chronic nimodipine alone on mu-opioid receptor binding was observed. These data indicate that NTX-induced upregulation and supersensitivity are independent of calcium channel blockade by nimodipine. These results contrast with those from tolerance and downregulation studies, and confirm suggestions that different substrates mediate chronic opioid agonist and antagonist-induced effects in vivo. Finally, in a separate study, morphine potency was unaffected by acute nimodiopine (100 microg/kg; SC), suggesting that prolonged exposure to this calcium channel blocker is required to increase morphine potency.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Lee
authors.forename: B C
authors.initials: BC
authors.lastname: Yoburn
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002121:Calcium Channel Blockers; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009553:Nimodipine; D009271:Naltrexone; D009020:Morphine