The interaction of metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH2) with 3H-dihydromorphine and 3H-D-Ala2-D-Leu5-enkephalin binding has been examined in rat brain homogenates. Displacements of both 3H-ligands by metkephamid indicate that metkephamid interacts competitively with greatest potency to the high affinity binding component for both ligands (mu1 site). Unlike most enkephalins and opiates, metkephamid binds equipotently to both morphine-selective (mu2) and enkephalin-selective (delta) binding sites. Metkephamid is differentiated from morphine by its better than 12-fold higher affinity for the delta receptor. Blockade of the high affinity (mu1) binding in vivo with high doses of naloxazone dramatically reduces metkephamid's analgesic potency.