OPIATE WITHDRAWAL SIGNS PRECIPITATED BY NALOXONE FOLLOWING A SINGLE EXPOSURE TO MORPHINE - POTENTIATION WITH A 2ND MORPHINE EXPOSURE

Recent studies in humans with no prior history of opiate abuse indicat ed that naloxone-precipitated signs of opiate withdrawal could be obse rved after a single exposure to morphine, and that the severity of wit hdrawal was enhanced following a second morphine exposure 24 h later. The current study was conducted to establish a paradigm in rodents tha t resembled these conditions described in humans. To that end, naloxon e-precipitated (0.03-3.0 mg/kg) suppression of operant response rates and somatic signs of withdrawal following single or repeated treatment s with morphine (5.0 mg/kg) were assessed in previously opiate-naive r ats. In one group of rats, naloxone was administered 4 h after both th e first and second morphine pretreatment, while in a separate group of rats naloxone was administered 4 h after the second morphine pretreat ment only. A single morphine pretreatment significantly increased nalo xone's potency to suppress operant response rates, and resulted in the precipitation by naloxone of certain somatic signs of withdrawal. The effects of naloxone on both dependent measures (operant response rate s and somatic signs) were potentiated following a second morphine pret reatment, regardless of whether naloxone was administered following bo th morphine exposures or only following the second morphine exposure. Thus, repeated morphine administration appears to be the critical fact or underlying the progressive increase in antagonist potency, whereas prior experience with naloxone is not a necessary factor. The results provide additional support for the hypothesis that the development of dependence on opiates is a progressive phenomenon that may begin with a single dosing.