Effects of chronic treatment with diazepam, phenobarbital, or amphetamine on naloxone-precipitated morphine withdrawal.

The present study examines the severity of naloxone-precipitated opiate withdrawal in morphine-pelleted rats and mice. Animals were chronically pretreated with either saline, diazepam, phenobarbital or amphetamine for 8 days prior to withdrawal precipitation. Indicators of withdrawal were changes in plasma corticosterone in rats and jumping behavior in mice. The use of chronic intravenous catheters in rats and one-way vision boxes allowed for serial blood sampling and sequential hormone determinations. Opiate dependence was established by the subcutaneous implantation of a 75-mg morphine pellet 72 h prior to withdrawal precipitation. All pretreated groups of rats with morphine pellets showed a substantial elevation of plasma corticosterone following the injection of naloxone (0.4 mg/kg, i.v.). Those with lactose pellets showed little change. The group pretreated with phenobarbital showed a lower, more attenuated withdrawal response as compared to saline or the other pretreated groups. The responsiveness of the hypothalamo-pituitary-adrenal axis to ether stress was evaluated. This was found to be unaffected by chronic phenobarbital suggesting that the drug may have a more specific effect on opiate dependence/withdrawal mechanisms. Similar studies in mice showed no differences in ED50 for naloxone-induced jumping behavior in any of the pretreatment groups.