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

Br J Pharmacol. 2001 Jun;133(3):438-44. doi: 10.1038/sj.bjp.0704092.


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 microg 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / pharmacology
  • Behavior, Animal / drug effects
  • Dinoprostone / analogs & derivatives
  • Dinoprostone / pharmacology*
  • Formaldehyde / pharmacology
  • Gene Deletion
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / metabolism
  • Mice
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Nitroprusside / pharmacology
  • Nitroso Compounds / pharmacology
  • Pain / chemically induced*
  • Pain / metabolism
  • Pain Measurement / drug effects
  • Reaction Time / drug effects
  • Receptors, Prostaglandin E / genetics
  • Receptors, Prostaglandin E / metabolism*
  • Receptors, Prostaglandin E, EP3 Subtype


  • Nitroso Compounds
  • ONO AE 248
  • Ptger3 protein, mouse
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP3 Subtype
  • 4-nitrosodimethylaniline
  • Nitroprusside
  • Formaldehyde
  • Nitric Oxide
  • Arginine
  • Dinoprostone