Role of prostaglandin receptor subtype EP1 in prostaglandin E2-induced nociceptive transmission in the rat spinal dorsal horn

It has been indicated that prostaglandin E-2 (PGE(2)) and the receptor for PGE2 (EP receptor) are key factors contributing to the facilitated generation of nociception. This study was designed to investigate the roles of PGE2 and EP, receptors in the spinal cord in the nociceptive transmission, using behavioral and intracellular calcium ion concentration ([Ca2+](i)) assays and in situ hybridization. Experiments were conducted on Sprague-Dawley rats. In behavioral assays, withdrawal thresholds to mechanical stimuli were evaluated using von Frey filament. The effect of an intrathecally administered selective EP1 antagonist, 6-[(2S,3S)-3-(4-chloro-2-methylphenyisulfonylaminomethyl)bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid (ONO-8711), on the intrathecal PGE(2)-induced hyperalgesia was examined. In [Ca2+] i assays, we measured [Ca2+](i) in the dorsal horn of spinal cord slices and examined the effects of PGE2 and ONO-8711 perfusion on the [Ca2+](i) changes. In situ hybridization using EP, digoxigenin probe was performed on the slice sections of the lumbar spinal cord and bilateral L-4 and L-5 dorsal root ganglions (DRGs). Mechanical hyperalgesia was observed after intrathecal PGE2 administration. Intrathecal administration of ONO-8711 attenuated the PGE(2)-induced mechanical hyperalgesia in a dose- and time-dependent manner. Perfusion of ONO-8711 markedly suppressed PGE(2)-induced [Ca2+](i) increment in laminae II-VI in dorsal horn of the spinal cord slice. Moreover, in situ hybridization revealed EP1 hybridization signals in the DRG neurons, but not in the spinal cord. The results of this study suggested that spinal PGE(2) activates the EP1 receptors existing on the central terminals of primary afferents, subsequently increasing in [Ca2+](i) in the spinal dorsal horn, which are involved in the mechanisms of spinal PGE(2)-induced nociceptive transmission. (C) 2004 Elsevier B.V. All rights reserved.