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of the short-acting -opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats.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

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Opiate‐dependence increases the reinforcing effects of remifentanil, a fast‐acting mu‐opioid receptor agonist, in rats. Chronic exposure to opiates also has been associated with changes in the number of opiate receptors in the brain and altered behavioral responses to opiates. Using cardiovascular activity as an endpoint to measure the physiological effects of remifentanil, this study investigated changes in the cardiovascular response to self‐administered remifentanil as a function of opiate dependence. Cardiovascular changes associated with self‐administered remifentanil (10, 32, and 100 ug/kg/inj) were recorded in morphine‐dependent and morphine‐naïve rats using a telemetry system. Self‐administered remifentanil produced dose‐dependent decreases in heart rate, which were immediately followed by compensatory increases. The initial decrease in heart rate was greater in morphine‐naïve rats, whereas the compensatory increases were greater in the morphine‐dependent rats, suggesting tolerance to the direct bradycardic effects of remifentanil and a sensitized response to the compensatory increase in heart rate. These findings suggest that the cardiovascular effects of remifentanil may serve as a potential index of physiological dependency produced by opiates.