Kappa- and delta-opioid agonists synergize to produce potent analgesia.

This study evaluated the interaction of the analgesic effects of a selective kappa- (U50, 488H) and a selective delta- ([D-Pen2,5]enkephalin, DPDPE) opioid agonist, co-injected intrathecally, using the Randall-Selitto paw-withdrawal test, in the rat. Intrathecal administration of both U50, 488H and DPDPE, as single agents, produced dose-dependent increases in mechanical nociceptive threshold. However, when the dose-response curves for both U50, 488H and DPDPE in the presence of a low-analgesic dose of the other agent were compared with the dose-response curves for the respective agonist administered alone, the curves for the combination regimens were shifted to the left. A statistically significant deviation from parallelism between the dose-response curves of the single versus the combined agents, as well as isobolographic analysis, demonstrates that the simultaneous administration of opioid agonists, the act at kappa- and delta-opioid receptor sites, can produce analgesic synergy.