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Vol. 298, Issue 3, 1193-1198, September 2001

Immunosuppression by delta -Opioid Antagonist Naltrindole: delta - and Triple µ/delta /kappa -Opioid Receptor Knockout Mice Reveal a Nonopioid Activity

Claire Gavériaux-Ruff, Dominique Filliol, Frédéric Simonin, Hans W. D. Matthes and Brigitte L. Kieffer

CNRS UPR 9050, ESBS, Université Louis Pasteur, Illkirch, France

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 /µ/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.

0022-3565/01/2983-1193$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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