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BEHAVIORAL PHARMACOLOGY

Morphine Deprivation Increases Self-Administration of the Fast- and Short-Acting µ-Opioid Receptor Agonist Remifentanil in the Rat

Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York (Z.D.C.); and Departments of Psychology (Z.D.C., J.H.W.) and Pharmacology (Y.N.-T.T., Y.-G.S., J.H.W.), University of Michigan, Ann Arbor, Michigan

Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting µ-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 µg/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.

Address correspondence to: Dr. Ziva D. Cooper, Substance Use Research Center, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032. E-mail: cooperz{at}pi.cpmc.columbia.edu