Previously we found that morphine's effects on locomotor activity and brain dopamine metabolism were enhanced in mice after cessation of 7-week oral nicotine treatment. In the present experiments we show that such chronic nicotine exposure cross-sensitizes NMRI mice to the reinforcing effect of morphine in the conditioned place preference paradigm. The nicotine-treated mice developed conditioned place preference after being conditioned twice with morphine 5 mg/kg s.c. whereas in control mice a higher dose (10 mg/kg) of morphine was required. Since the reinforcing effect of morphine is mediated via micro-opioid receptors we used [3H]DAMGO autoradiography to study whether the number (B(max)) or affinity (K(D)) of mu-opioid receptors in the mouse brain are affected following chronic nicotine exposure. However, no changes were found in the number or affinity of micro-opioid receptors in any of the brain areas studied. Neither did we find alterations in the functional activity of mu-opioid receptors studied by [35S]GTPgammaS-binding. In conclusion, chronic oral nicotine treatment augments the reinforcing effects of morphine in mice, and this cross-sensitization does not seem to be mediated by micro-opioid receptors.