Characterization of the antinociceptive effects of TRK-820 in the rat

Abstract

We have already reported that TRK-820, (−)-17-cyclopropylmethyl-3,14 b-dihydroxy-4,5 a-epoxy-6 b-[ N-methyl- trans-3-(3-furyl)acrylamido]morphinan hydrochloride, a new selective κ-opioid receptor agonist, has affinity for κ-subtype opioid receptors other than the κ 1-opioid receptor. It would be of interest to examine whether the different κ-opioid receptor subtype properties of TRK-820 participate in its antinociceptive action in the inflamed paw test and the formalin test. TRK-820 produced a potent antinociceptive effect, which was inhibited by the selective κ-opioid receptor antagonist nor-binaltorphimine, but not by the μ-opioid receptor antagonist naloxone in the mechanical paw pressure test. TRK-820 also produced a potent antinociceptive effect in rats with adjuvant-induced arthritis. TRK-820 and morphine, a prototype μ-opioid receptor agonist, were equally effective in inhibiting the nociceptive responses in the arthritic rats and in the normal rats, while ICI-199441, 2-(3,4-dichlorophenyl)- N-methyl- N-[(1 S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide, a κ-opioid receptor agonist, was about 5-fold less potent in the arthritic rats than in the normal rats. In the formalin test TRK-820 had a very similar antinociceptive potency to that of ICI-199441, unlike in the arthritic rats in which TRK-820 was 2.5 times more potent than ICI-199441. It is concluded that TRK-820 produced a potent antinociceptive action via the stimulation of κ-opioid receptors in rats. TRK-820 has a unique antinociceptive profile different from that of the other κ-opioid receptor agonists such as ICI-199441 in arthritic rats.