The Synergistic Antinociceptive Interactions of Endomorphin-1 with Dexmedetomidine and/or S(+)-Ketamine in Rats

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UNLABELLED: Spinal administration of the endogenous mu-opioid agonist peptide, endomorphin-1, results in antinociception in rodents, but there are few data about its interaction with other antinociceptive drugs. We investigated the antinociceptive interactions at the spinal level of endomorphin-1 with the N-methyl-D-aspartate antagonist S(+)-ketamine, the alpha2-adrenoceptor agonist dexmedetomidine, or both in awake rats. Nociception was assessed by the tail-flick test. Dose-response curves were determined for endomorphin-1 (0.6-50 microg), for dexmedetomidine (0.1-10 microg), for mixtures of S(+)-ketamine (30 or 100 microg) with endomorphin-1 (2-18 microg) or of endomorphin-1 with dexmedetomidine in a fixed ratio (4:1), and for the triple combination of the three drugs after intrathecal administration. Endomorphin-1 and dexmedetomidine both produced dose-dependent antinociception. The coadministration of 100 microg S(+)-ketamine significantly enhanced the antinociceptive effect of 6 microg endomorphin-1. Isobolographic analysis of the combinations of endomorphin-1 and dexmedetomidine revealed a synergistic interaction between these drugs. The 80% effective dose for the triple combination was significantly less than that for either binary combination. These data indicate that S(+)-ketamine and dexmedetomidine, acting via different receptors, produce synergistic antinociceptive interaction with endomorphin-1 at the spinal level. Furthermore, the triple combination of an opioid agonist, an alpha2-adrenoceptor agonist, and an N-methyl-D-aspartate receptor antagonist shows potent antinociceptive activity. IMPLICATIONS: The coadministration of the N-methyl-D-aspartate antagonist receptor antagonist, S(+)-ketamine, or the specific alpha2-adrenoceptor agonist, dexmedetomidine, significantly enhances the antinociceptive effect of the endogenous mu-opioid agonist, endomorphin-1, at the spinal level. The triple combination of the three drugs causes a further improved antinociception.

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