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of the short-acting -opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats.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

RationaleAlthough it is known that humans will self‐administer intravenous nicotine, the motivational valences of nicotine are not well understood. In order to address the seeming paradox involving the positive and negative subjective effects of nicotine, we have developed operant choice procedures that allow us to detect when intravenous nicotine results in both increases and decreases in behavior resulting in its self‐administration.ObjectiveTo examine the effects of contingent and non‐contingent intravenous nicotine on sucrose‐maintained operant responding.MethodsThe effects of intravenous nicotine on sucrose maintained behavior in a two‐lever operant chamber was measured in rats.ResultsResponse‐contingent nicotine dose‐dependently decreased sucrose maintained‐behavior in our operant choice procedures, and when available, nicotine increased responding maintained by only sucrose alternative consequence. Delay in response‐contingent nicotine attenuated the punishing effect of nicotine. Non‐contingent nicotine, at total cumulative doses equal to and above those self‐administered did not punish sucrose‐maintained behavior.ConclusionIntravenous nicotine may serve as a punisher of sucrose‐maintained behavior in rats. University of Michigan Rackham Merit Fellowship.