Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal

Rationale. Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids. Objective. The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine. Methods. Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003-16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h). Results. Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles. Conclusions. CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.