Characterization of EP receptor subtypes responsible for prostaglandin E2‐induced pain responses by use of EP1 and EP3 receptor knockout mice
Open Access
- 1 June 2001
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 133 (3) , 438-444
- https://doi.org/10.1038/sj.bjp.0704092
Abstract
Prostaglandin E2 (PGE2) 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. PGE2 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 EP1 receptors appears to be upstream, rather than downstream, of NMDA receptor activation and NO production in the PGE2‐induced allodynia. Although PGE2 produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 μg 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. Saline‐injected EP1−/− mice showed hyperalgesia, which was reversed by i.t. PGE2 in a dose‐dependent manner. There was no significant difference in the formalin‐induced behaviours between EP1−/− or EP3−/− mice and the cognate wild‐type mice. These results demonstrate that spinal EP1 receptors are involved in the PGE2‐induced allodynia and that spinal EP3 receptors are involved in the hyperalgesia induced by low doses of PGE2. However, the formalin‐induced pain cannot be ascribed to a single EP receptor subtype EP1 or EP3. British Journal of Pharmacology (2001) 133, 438–444; doi:10.1038/sj.bjp.0704092Keywords
This publication has 26 references indexed in Scilit:
- Stimulation of nitric oxide release from rat spinal cord by prostaglandin E2British Journal of Pharmacology, 1998
- Prostaglandin E2 stimulates glutamate release from synaptosomes of rat spinal cordNeuroscience Letters, 1995
- Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2α in conscious micePain, 1995
- Involvement of glutamate receptors in allodynia induced by prostaglandins E 2 and F 2α injected into conscious micePain, 1994
- Allodynia evoked by intrathecal administration of prostaglandin E2 to conscious micePain, 1994
- Hyperalgesia Mediated by Spinal Glutamate or Substance P Receptor Blocked by Spinal Cyclooxygenase InhibitionScience, 1992
- Nociceptive effects induced by intrathecal administration of prostaglandin D2, E2, or F2α to conscious miceBrain Research, 1990
- The formalin test in mice: dissociation between inflammatory and non-inflammatory painPAIN®, 1987
- Ethical guidelines for investigations of experimental pain in conscious animalsPAIN®, 1983
- Intrathecal morphine in mice: A new techniqueEuropean Journal of Pharmacology, 1980