Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation.

Abstract

The pain mediator prostaglandin E2 (PGE2) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to Gs proteins and increase cAMP. However, PGE2 also activates EP3 receptors, and the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via Gi proteins. This opposite effect raises the intriguing question of whether the Gi-protein-coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE2. We found extensive localization of the EP3 receptor in primary sensory neurons and the spinal cord. The selective activation of the EP3 receptor at these sites did not sensitize nociceptive neurons in healthy animals. In contrast, it produced profound analgesia and reduced responses of peripheral and spinal nociceptive neurons to noxious stimuli but only when the joint was inflamed. In isolated dorsal root ganglion neurons, EP3 receptor activation counteracted the sensitizing effect of PGE2, and stimulation of excitatory EP receptors promoted the expression of membrane-associated inhibitory EP3 receptor. We propose, therefore, that the EP3 receptor provides endogenous pain control and that selective activation of EP3 receptors may be a unique approach to reverse inflammatory pain. Importantly, we identified the EP3 receptor in the joint nerves of patients with painful osteoarthritis.

• Authors: Gabriel Natura, Karl-Jürgen Bär, Annett Eitner, Michael K Boettger, Frank Richter, Susanne Hensellek, Andrea Ebersberger, Johannes Leuchtweis, Takayuki Maruyama, Gunther Olaf Hofmann, Karl-Jürgen Halbhuber, Hans-Georg Schaible
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 33 Pg. 13648-53 (Aug 13 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23904482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Receptors, Prostaglandin E, EP3 Subtype

Topics

• Analysis of Variance
• Animals
• DNA Primers (genetics)
• Humans
• Immunohistochemistry
• Inflammation (physiopathology)
• Joints (physiopathology)
• Nociception (physiology)
• Nociceptors (metabolism)
• Osteoarthritis (physiopathology)
• Patch-Clamp Techniques
• Polymerase Chain Reaction
• Polymorphism, Restriction Fragment Length
• Rats
• Rats, Inbred Lew
• Receptors, Prostaglandin E, EP3 Subtype (metabolism)