• K Fujibayashi and Y Iizuka.
• Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
• Jpn. J. Pharmacol. 1995 May 1; 68 (1): 57-63.

AbstractThe antinociceptive effect of a selective kappa-opioid receptor agonist R-84760, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride, in the second phase of the formalin test, a model of tonic pain, was examined in mice. R-84760 had a 2700 times more potent antinociceptive effect than morphine. The effect of R-84760 was antagonized by subcutaneously administered nor-binaltorphimine, a kappa-selective opioid receptor antagonist. Both intracerebroventricularly and intrathecally administered nor-binaltorphimine partially antagonized the antinociceptive effect of R-84760. Intrathecally administered phentolamine, an alpha-adrenoceptor antagonist, attenuated and desipramine, a noradrenaline reuptake inhibitor, augmented the antinociceptive effect of R-84760. Intrathecally administered noradrenaline attenuated the nociceptive response in the second phase of the formalin test. Intrathecally administered (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), an N-methyl-D-aspartate (NMDA)-receptor antagonist, reduced and threo-beta-hydroxyaspartate, a reuptake inhibitor of glutamate, augmented the second phase nociceptive response. However, R-84760 did not influence the intrathecally injected NMDA-induced nociceptive response. These results suggest the following: R-84760 produces an extremely potent antinociceptive effect against tonic pain through the kappa-opioid receptors; the sites of action of subcutaneously administered R-84760 are the supraspinal and spinal loci in the central nervous system; and a part of the mechanism of the antinociceptive effect of R-84760 is activation of the descending noradrenergic pathway.

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