The opioid system has been implicated in mood disorders as well as in the mechanism of action of antidepressants. Since the opioid component in venlafaxine (VLX) is still a matter of discussion, we investigated the role of opioid receptors in the antidepressant-like effect of VLX in the forced swimming test in mice. The non-selective opiate antagonist naloxone at high dose (2 mg/kg, s.c.) antagonized the effect of VLX. In contrast, beta-funaltrexamine (40 mg/kg, s.c.), which preferentially blocks mu(1)/mu(2) opioid receptors, naloxonazine (35 mg/kg, s.c.), a selective mu(1) opioid antagonist, naltrindole (10 mg/kg, s.c.), a selective delta opioid antagonist, and Nor-binaltorphimine (10 mg/kg, s.c.), which selectively blocks kappa-opioid receptors, were all ineffective. Thus, although apparently mediated by the opioid system, the behavioural effect of VLX does not involve specific opioid receptors.