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PAIN MEDICINE

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

Gyöngyi Horvath, MD PhD^*, Gabriella Joo, PhD, Ildiko Dobos, Walter Klimscha, MD, Geza Toth, PhD, and György Benedek, MD DSc

*Department of Physical Therapy, Faculty of Health Science, and Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary; Department of Anesthesiology and Intensive Care, University of Vienna, Austria; and Isotope Laboratory of Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary

Address correspondence and reprint requests to Gyöngyi Horvath, Department of Physiology, Faculty of Medicine, University of Szeged, P.O.B: 427; H-6701, Szeged, Hungary. Address e-mail to horvath{at}phys.szote.u-szeged.hu

Spinal administration of the endogenous µ-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 ₂-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 µg), for dexmedetomidine (0.1–10 µg), for mixtures of S(+)-ketamine (30 or 100 µg) with endomorphin-1 (2–18 µg) 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 µg S(+)-ketamine significantly enhanced the antinociceptive effect of 6 µg 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 ₂-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 ₂-adrenoceptor agonist, dexmedetomidine, significantly enhances the antinociceptive effect of the endogenous µ-opioid agonist, endomorphin-1, at the spinal level. The triple combination of the three drugs causes a further improved antinociception.

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