This study addressed the opiate receptor subclass which underlies the paradoxical analgesic action of intrathecal administration of low doses of the stereospecific opiate receptor antagonist, naloxone. The analgesic effect of low dose naloxone was abolished in rats that had been pretreated 24 hr earlier with a large intrathecal dose of naloxone or 20 min previously with the delta receptor specific antagonist, ICI-174,864. A large intrathecal dose of naloxone administered 24 hr previously also abolished the analgesic effects of the delta-specific ligands [D-Pen2,5]-enkephalin and [D-Ser2]-Leu enkephalin-Thr but not those produced by mu-ligands Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and beta-Casomorphin(1-4) amide or by the kappa-specific ligand, U50,488H. Furthermore, the analgesic action of low dose naloxone (on thermal and mechanical nociceptive threshold tests) persisted in rats made tolerant to mu-opioid receptor specific ligands. We conclude that the analgesic action of a low dose of naloxone is mediated via interaction with a stereospecific binding site with the characteristics of the delta-opioid receptor.