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.
Miaskowski
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School of Nursing, University of California, San Francisco 94143.
Taiwo
Y O
YO
Levine
J D
JD
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa
D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-