Peripheral antinociceptive effect of 2-arachidonoyl-glycerol and its interaction with endomorphin-1 in arthritic rat ankle joints.

Clinical and experimental pharmacology & physiology 2009 Dec 23; In press

Mecs L, Tuboly G, Toth K, Nagy E, Nyari T, Benedek G, Horvath G

Department of Physiology, Faculty of Medicine, University of Szeged, P.O.Box 427, H-6701 Szeged, Hungary.

Abstract 1. Both cannabinoid and opioid receptors are localized at peripheral level, and drugs acting on these receptors may produce antinociception after topical administration, however, the effect of endogenous ligands at these receptors is poorly clarified. Our goal was to determine the antinociceptive potency of the endogenous cannabinoid 2-arachidonoyl-glycerol (2-AG), and its interaction with endomorphin-1 (EM1) at joint level in the rat inflammation model. 2. Mechanical hypersensitivity was produced by injection of carrageenan (300 mug/30mul) into the tibiotarsal joint of the right hind leg. The mechanical threshold was assessed by von Frey filaments. 2-AG (3-200 mug), EM1 (100-300 mug) and their combinations in a fixed-dose ratio (1:10) were given into the inflamed joint, and the threshold was determined repeatedly for 105 min after the drug administrations. 3. Both ligands produced dose-dependent anti-hyperalgesia, and the highest doses caused prolonged effect, but they did not influence the degree of oedema and the withdrawal threshold at the non-inflamed side. EM1 had lower potency compared to 2-AG (ED(25): 233 [CI:198-268] mug and 126 [CI:88-162] mug, respectively; p<0.05). The effects of EM1 and 2-AG were prevented by mu-opioid and cannabinoid 1 receptor antagonists, respectively. The ED(25) value for the combination (98 [CI:80-112] mug) did not differ significantly from the value of 2-AG, however, the largest dose combination produced a significantly higher effect than the ligands by themselves. 4. Our data showed that 2-AG was an effective antinociceptive ligand at joint level, and its combination with EM1 produced long-lasting, effective antinociception.

Keywords: arthritis