Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice

1 Prostaglandin E-2 (PGE(2)) is known to be the principal pro-inflammatory prostanoid and play an important role in nociception. To identify PGE receptor (EP) subtypes that mediate pain responses to noxious and innocuous stimuli, we studied them by use of EP1 and EP3 knockout (EP1- - and EP3- -) mice. 2 PGE(2) could induce mechanical allodynia in EP1+ +, EP3+ + and EP3- - mice, but not in EP1- - mice. N-methyl-D-aspartate (NMDA), the substrate of nitric oxide (NO) synthase L-arginine. or the NO donor sodium nitroprusside administered intrathecal (i.t.) could induce allodynia in EP3- - and EP1- - mice. Activation of EPI receptors appears to be upstream, rather than downstream of NMDA receptor activation and NO production in the PGE(2)-induced allodynia. 3 Although PGE(2) produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 mug kg(-1) in EP3+ + mice, it showed a monophasic hyperalgesic action at 5 ng kg(-1) or higher doses in EP3- - mice. The selective EP3 agonist, ONO-AE-248, induced hyperalgesia at 500 pg kg(-1) in EP3+ + mice, but not in EP3-.- mice. 4 Saline-injected EP1- - mice showed hyperalgesia, which was reversed by i.t. PGE(2) in a dose-dependent manner. 5 There was no significant difference in the formalin-induced behaviours between EP1- - or EP3- - mice and the cognate wild-type mice. 6 These results demonstrate that spinal EP1 receptors an involved in the PGE(2)-induced allodynia and that spinal EP3 receptors are involved in the hyperalgesia induced by low doses of PGE(2). However, the formalin-induced pain cannot be ascribed to a single EP1 receptor subtype EP1 or EP3.