Characterization of EP receptor subtypes responsible for prostaglandin E 2 ‐induced pain responses by use of EP 1 and EP 3 receptor knockout mice

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 EP 1 and EP 3 knockout (EP 1 −/− and EP 3 −/− ) mice. PGE 2 could induce mechanical allodynia in EP 1 +/+ , EP 3 +/+ and EP 3 −/− mice, but not in EP 1 −/− 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 EP 3 −/− and EP 1 −/− mice. Activation of EP 1 receptors appears to be upstream, rather than downstream, of NMDA receptor activation and NO production in the PGE 2 ‐induced allodynia. Although PGE 2 produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 μg kg −1 in EP 3 +/+ mice, it showed a monophasic hyperalgesic action at 5 ng kg −1 or higher doses in EP 3 −/− mice. The selective EP 3 agonist, ONO‐AE‐248, induced hyperalgesia at 500 pg kg −1 in EP 3 +/+ mice, but not in EP 3 −/− mice. Saline‐injected EP 1 −/− mice showed hyperalgesia, which was reversed by i.t. PGE 2 in a dose‐dependent manner. There was no significant difference in the formalin‐induced behaviours between EP 1 −/− or EP 3 −/− mice and the cognate wild‐type mice. These results demonstrate that spinal EP 1 receptors are involved in the PGE 2 ‐induced allodynia and that spinal EP 3 receptors are involved in the hyperalgesia induced by low doses of PGE 2 . However, the formalin‐induced pain cannot be ascribed to a single EP receptor subtype EP 1 or EP 3 .British Journal of Pharmacology (2001) 133 , 438–444; doi: 10.1038/sj.bjp.0704092