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of the short-acting mu-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats.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 mug/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.

Fig. 1

Average change in body weight from baseline weight (±S.E.M.) measured every 12 h in control (○, baseline weight = 289 ± 10 g), MD (●, baseline weight = 336.5 ± 19 g), and MW (■, baseline weight = 344 ± 7 g) rats self-administering 0.8 μg/kg/infusion remifentanil and control rats (□, baseline weight = 315 ± 5 g) self-administering 0.4 μg/kg/infusion. Weights of the dependent groups were significantly less than the control group after the 4th self-administration session (p ≤ 0.05), an effect that persisted until the termination of the experiment. Weights from the two control groups did not differ.

Fig. 2

Average (±S.E.M.) responding for control (□), MD (●), and MW (■) groups for 0.4 (a), 0.8 (b), 1.6 (c), 3.2 (d), and 6.4 (e) μg/kg/infusion over 20 self-administration sessions. #, difference between control and MD (#, p ≤ 0.05; ##, p ≤ 0.01; ###, p ≤ 0.001). *, difference between control and MW (*, p ≤ 0.05; **, p ≤ 0.01;***, p ≤ 0.001).

Fig. 3

Average (±S.E.M.) responding for (a) and intake of (b) remifentanil in control (□), MD (●), and MW (■) groups on the final self-administration session. Dose-dependent responding and intake were observed for all three groups. Suppressed responding was observed in the MD group, whereas enhanced responding and intake were observed in the MW rats. *, difference between control and MW (*, p ≤ 0.05; **, p ≤ 0.01; ***, p ≤ 0.001). $, difference between MD and MW groups ($$, p ≤ 0.01; $$$, p ≤ 0.001).

Fig. 4

Average AUC (±S.E.M.) analysis of remifentanil self-administration dose-response functions generated from control (□), MD (●), and MW (■) groups according to session. #, difference between control and MD groups (#, p ≤ 0.05; ##, p ≤ 0.01). *, difference between control and MW groups (**, p ≤ 0.01; ***, p ≤ 0.001).