Naltrexone-induced conditioned place aversion following a single dose of morphine in the rat

Limited preclinical research has been conducted investigating the motivational or “affective” properties of withdrawal from acute opioid dependence following a single morphine exposure. Therefore, the purpose of the present study was to pharmacologically characterize the motivational properties associated with naltrexone-precipitated withdrawal after a single injection of morphine using place conditioning. Conditioned place aversion was assessed using a biased two-compartment apparatus and procedure. Adult male Sprague-Dawley rats were given 15 min free access to the entire apparatus on day one to determine initial preferences. Beginning on the second day, combinations of either saline or morphine (1.0-10 mg/kg, s.c.) followed by naltrexone (0.003-3.0 mg/kg, s.c.) 3.75 h later were administered. Rats were then immediately confined to one compartment for 30 min. The next day, rats received the alternative treatment and were confined to the opposite compartment. Twenty-four hours later animals were tested again for 15 min while they had access to the entire apparatus. Morphine followed by naltrexone conditioned significant place aversion (CPA) with just one pairing. This effect was a function of the naltrexone and morphine doses. CPA was also dependent on morphine pretreatment time, with significant aversion only occurring 4 h after morphine pretreatment. Finally continuous morphine administration followed by a single injection of naltrexone resulted in CPA. These data extend the range of behavioral effects associated with antagonist-precipitated withdrawal from acutely administered morphine and suggest that place conditioning is an effective model in assessing motivational aspects of withdrawal from acute opioid dependence in rats.