Opioid peptides have been shown by several studies to modulate various parameters of the immune response, but scant experimental findings exist on the role played by specific opioid receptor subtypes in the control of immune mechanisms. This study focuses on the in vitro influences of [Trp4,Asn7]der-morphin, aμ-selective agonist, [D-Ala2]deltorphin I, aδ-selective agonist and U50,488, aκ-selective agonist, on the proliferative response of splenocytes to concanavalin A (Con A). [Trp4, Asn7]dermorphin at low concentrations (10–11and 10-12M)enhanced the proliferative response to Con A, whereas higher concentrations (10–6to 10–7M) inhibited it. Both effects were antagonized by naloxone. [D-Ala2]deltorphin I at very low concentrations (10–12to 10–13M) also produced a significant increase in the proliferative response of splenocytes to Con A. This effect was significantly antagonized by natrindole, a specific δ-receptor antagonist. Finally U50,488 at concentrations ranging from 10–8to 10–9Minhibited the proliferative response to Con A. The effects of U50,488 were mediated by the stimulation of theκ-opioid receptors, since a preincubation of splenocytes with the selective antagonist norbinaltorphimine significantly reduced or abolished the U50,488-induced suppression of the mitotic response. In conclusion, our results clearly indicate that the different opioid receptor subtypes play a different role in the control of immune mechanisms and suggest that immunoenhancing effects of opioid peptides are very likely due to the stimulation of μ- and δ-receptors, whereas the immunosuppressive effects are mediated through the stimulation ofκ-opioid receptors.