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 re jection in vivo and suppress allogeneic mixed lymphocyte reaction (MLR) in vitro, similarly to cyclosporin A. We investigated whether this action is m ediated by delta -opioid receptors using both genetic and pharmacological t ools. Naltrindole and two related compounds, 7-benzylidene-7-dehydronaltrex one and naltriben, inhibited MLR performed with lymphocytes from wild-type and delta -opioid receptor knockout mice, with comparable potency. Furtherm ore, these compounds suppressed the proliferation of spleen cells from trip le 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 t he MLR assay. In conclusion, we demonstrate for the first time that the imm unosuppressive activity of naltrindole and close derivatives is not mediate d by any of the three cloned opioid receptors. Therefore, the postulated in hibitory activity of naltrindole in the graft rejection process is mediated by a target, which remains to be discovered.