title: 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.affiliation: Institute of Physiology I, Jena University Hospital, Friedrich Schiller University Jena, 07740 Jena, Germany.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Natura
authors.forename: Karl-Jürgen
authors.initials: KJ
authors.lastname: Bär
authors.forename: Annett
authors.initials: A
authors.lastname: Eitner
authors.forename: Michael K
authors.initials: MK
authors.lastname: Boettger
authors.forename: Frank
authors.initials: F
authors.lastname: Richter
authors.forename: Susanne
authors.initials: S
authors.lastname: Hensellek
authors.forename: Andrea
authors.initials: A
authors.lastname: Ebersberger
authors.forename: Johannes
authors.initials: J
authors.lastname: Leuchtweis
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Gunther Olaf
authors.initials: GO
authors.lastname: Hofmann
authors.forename: Karl-Jürgen
authors.initials: KJ
authors.lastname: Halbhuber
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology*; D007596:Joints / Q000503:physiopathology; D059225:Nociception / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism*; D010003:Osteoarthritis / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D051381:Rats; D011917:Rats, Inbred Lew; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D058308:Receptors, Prostaglandin E, EP3 Subtype
keywords: mechanical hyperalgesia; sodium currents
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