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ANALGESIA

The Peripheral Antinociceptive Effects of Endomorphin-1 and Kynurenic Acid in the Rat Inflamed Joint Model

Laszlo Mecs, MD^*, Gabor Tuboly, MD, Endre Nagy, MD, Gyorgy Benedek, MD, DSc, and Gyongyi Horvath, MD, DSc

From the *Department of Orthopedics, University of Szeged, Department of Physiology, University of Szeged, and Department of Radiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.

Address correspondence and reprint requests to Gyongyi Horvath, MD, DSc, Department of Physiology, Faculty of Medicine, University of Szeged, PO Box 427; H-6701, Szeged, Hungary. Address e-mail to horvath{at}phys.szote.u-szeged.hu.

Abstract

BACKGROUND: Several data suggest that both opioid and N-methyl-d-aspartate (NMDA) receptors are localized at the peripheral level, and drugs acting on these receptors may produce antinociception after topical administration; however, the antinociceptive effect of endogenous ligands at these receptors is poorly clarified. Our goal in this study was to determine the antinociceptive potency of the endogenous opioid peptide, endomorphin-1 (EM1), and the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and their interaction at the peripheral level in the rat inflamed joint model.

METHODS: Mechanical hypersensitivity was produced by injection of carrageenan (300 µg/20 µL) into the tibiotarsal joint of the right hind leg. The mechanical pain threshold was assessed by von Frey filaments (0.064-110 g). EM1 (30, 100, and 200 µg), KYNA (30, 100, 200, and 400 µg), and their combinations in a fixed-dose ratio (1:1) were injected into the inflamed joint, and the pain threshold was determined repeatedly for 75 min after the drug administrations.

RESULTS: Neither EM1 nor KYNA administered to the inflamed joint influenced the pain threshold at the noninflamed side. Both ligands produced dose-dependent antihyperalgesia, and the highest doses caused a prolonged effect. EM1 had higher potency (30% effective dose [ED₃₀] and 50% effective dose [ED₅₀] values were 112 µg [confidence interval {CI}: 80-146] and 167 µg [CI: 135-220], respectively) compared with KYNA (ED₃₀ and ED₅₀ values were 204 µg [CI: 160-251] and 330 µg [CI: 280-407], respectively). The antinociceptive effect of EM1 was prevented by subcutaneous naltrexone pretreatment. The coadministration of EM1 with KYNA caused an enhanced and/or prolonged antinociceptive effect. The ED₃₀ and ED₅₀ values of the combination were 141 µg [CI: 83-182] and 231 µg [CI: 190-293], respectively, which did not differ significantly from the theoretically additive values (ED₃₀ and ED₅₀ values were 145 µg [CI: 68-237] and 220 µg [CI: 144-230], respectively), thus the interaction between these ligands is additive. None of the treatments caused any sign of side effects.

CONCLUSION: Peripherally administered endogenous opioid agonist and NMDA receptor antagonist ligands might be beneficial in inflammatory pain. Because both drugs barely cross the blood-brain barrier, their local administration causes no central side effects.