Activation of the opioid μ1, but not δ or κ, receptors is required for nicotine reinforcement in a rat model of drug self-administration.

There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the μ1, the δ, and the κ opioid receptors. Male Sprague-Dawley rats were trained in daily 1h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for μ1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for δ receptors, 0, 0.5 and 5mg/kg), and 5'-guanidinonaltrindole (GNTI, selective for κ receptors, 0, 0.25 and 1mg/kg). In each individual drug group, the 3 drug doses were tested by using a within-subject and Latin-Square design. The effects of these antagonists on food self-administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid μ1, but not the δ or the κ, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the μ1 receptors would be a promising target for the development of opioid ligands for smoking cessation.