BACKGROUND The role played by endogenous opioids in mediating the reinforcing properties of nicotine is unclear. As with preclinical studies, clinical trials with naloxone, a prototypic opioid receptor antagonist have yielded equivocal findings with regard to its efficacy in reducing cigarette smoking. OBJECTIVE The aim of the present study was to examine the effects of three opioids that exhibit relative selectivity at mu-, kappa- and delta-opioid receptors on nicotine self-administration in male hooded Lister rats. METHODS Graded doses (0.3, 1.0, and 3.0 mg/kg IP) of each opioid agonist or antagonist were tested in different groups of rats repeatedly over three consecutive nicotine intravenous nicotine-self administration (0.03 mg/kg/infusion) sessions. The same treatments were tested in parallel groups of rats trained to respond for food reinforcement. RESULTS Naloxone was very effective in attenuating the levels of nicotine self-administered across all doses tested. The selective kappa-opioid receptor agonist U50,488, reduced nicotine self-administration in doses of 1 and 3 mg/kg, while the 0.3 mg/kg dose produced a small increase in nicotine intake. Finally, the specific delta-opioid receptor antagonist, naltrindole did not significantly modify nicotine self-administration behaviour. In contrast, all three opioids failed to modify behaviour maintained by food reinforcement. CONCLUSIONS These findings suggest endogenous opioids are crucial in mediating the reinforcing effects of nicotine and that the mu-opioid receptor subtype may represent a potential target for selectively reducing nicotine-taking behaviour as part of a pharmacological approach to develop smoking cessation aids.