Immunosuppression by delta-opioid antagonist naltrindole: delta- and triple mu/delta/kappa-opioid receptor knockout mice reveal a nonopioid activity.

The delta-opioid antagonist naltrindole has been shown to inhibit graft rejection in vivo and suppress allogeneic mixed lymphocyte reaction (MLR) in vitro, similarly to cyclosporin A. We investigated whether this action is mediated by delta-opioid receptors using both genetic and pharmacological tools. Naltrindole and two related compounds, 7-benzylidene-7-dehydronaltrexone and naltriben, inhibited MLR performed with lymphocytes from wild-type and delta-opioid receptor knockout mice, with comparable potency. Furthermore, these compounds suppressed the proliferation of spleen cells from triple delta/mu/kappa-opioid receptor-deficient animals as well. Finally, the highly delta-selective, but structurally distinct, antagonist N,N-dimethyl-Dmt-Tic-OH and the general opioid antagonist naltrexone were inactive in the MLR assay. In conclusion, we demonstrate for the first time that the immunosuppressive activity of naltrindole and close derivatives is not mediated by any of the three cloned opioid receptors. Therefore, the postulated inhibitory activity of naltrindole in the graft rejection process is mediated by a target, which remains to be discovered.