Received for publication March 20, 2008.
Revised May 22, 2008.
Accepted for publication May 28, 2008.

Morphine deprivation increases self-administration of the fast- and short-acting mu-opioid receptor agonist remifentanil in the rat

Abstract

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of the short-acting µ-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats.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, hours 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-hour sessions, either 12 or 24 hours after the maintenance dose of morphine. Compared to 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 to 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.

Key words: dependence, deprivation, morphine, opiate, remifentanil, self-administration