The effect of nimodipine on opioid antagonist-induced upregulation and supersensitivity

Regulation of calcium flux has been suggested to play a role in acute and c hronic effects of opioids. Previous studies have shown calcium channel bloc kers can inhibit opioid agonist induced downregulation of mu-opioid recepto rs and may reduce the magnitude of tolerance. In the present study, we dete rmined if calcium channel blockade would affect increases in opioid recepto r density and functional supersensitivity produced by chronic opioid antago nist treatment in the mouse. Mice were implanted subcutaneously with a 15-m g naltrexone (NTX) or placebo pellet. Mice also were implanted with an osmo tic minipump that infused nimodipine (100 mu g/kg/day) or a second placebo pellet. This protocol yielded four groups: nimodipine-NTX; nimodipine-place bo; placebo-NTX; placebo-placebo. On the seventh day, pumps and pellets wer e removed. Twenty-four hours later, a morphine dose-response study was cond ucted (tail flick); or mice were sacrificed and saturation binding studies ([H-3]DAMGO) were performed in whole brain. NTX treatment significantly inc reased the analgesic potency of morphine by similar to 60%. Nimodipine incr eased the potency of morphine by similar to 50%. For mice treated with both nimodipine and NTX, there was an additive effect on morphine potency (simi lar to 120% increase). In binding studies, NTX increased the density of mu- opioid receptors similarly (similar to 60-70%) in the presence and absence of nimodipine treatment, with no change in affinity. No effect of chronic n imodipine alone on mu-opioid receptor binding was observed. These data indi cate that NTX-induced upregulation and supersensitivity are independent of calcium channel blockade by nimodipine. These results contrast with those f rom tolerance and downregulation studies, and confirm suggestions that diff erent substrates mediate chronic opioid agonist and antagonist-induced effe cts in vivo. Finally, in a separate study, morphine potency was unaffected by acute nimodiopine (100 mu g/kg; SC), suggesting that prolonged exposure to this calcium channel blocker is required to increase morphine potency. ( C) 2000 Elsevier Science Inc.