Development, extinction and reinstatement of morphine withdrawal-induced conditioned place aversion in rats

The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-based process. Here, we used conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal to measure the aversive effects. Using an unbiased conditioning paradigm, we treated rats with morphine hydrochloride [(10 mg/kg intraperitoneally (i.p.)] twice per day (at 08:00 and 20:00) for 6.5 days (from day 1 to day 7 morning), while gave them naloxone (0.3 mg/kg i.p.) on day 6, a precipitated withdrawal paired with a compartment that caused CPA to the side. Then, the rats exhibited CPA were received 12 extinction trials from days 7 to 13, by daily exposed to the two compartments for free exploration. On day 13, the rats with extinguished CPA were treated with a priming injection of morphine (10 mg/kg i.p.) followed by naloxone (0.3 mg/kg i.p.) that reliably reinstated CPA. These results demonstrated that repeatedly morphine-treated rats showed the formation, extinction and reinstatement of CPA. The present CPA model induced by these procedures may be useful for studying the biological mechanisms underlying the aversive motivational component of opiate withdrawal.