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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 11, 2006; DOI: 10.1124/jpet.106.105569

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Received for publication April 3, 2006.
Revised August 31, 2006.
Accepted for publication September 7, 2006.

Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity

Chung-Ren Lin 1, Fumimasa Amaya 1, Lee B. Barrett 1, Haibin Wang 1, Tarek Samad 1, Junji Takada 2, Clifford J. Woolf 1*

1 Massachusetts General Hospital 2 Pfizer Global Research and Development

* Address correspondence to: E-mail: woolf.clifford{at}mgh.harvard.edu

Abstract

Prostaglandin E2 (PGE2) is both an inflammatory mediator released at the site of tissue inflammation and a neuromodulator that alters neuronal excitability and synaptic processing. The effects of PGE2 are mediated by four G-protein-coupled EP receptors (EP1-EP4). Here we show that the EP4 receptor subtype is expressed by a subset of primary sensory dorsal root ganglion (DRG) neurons and that its levels, but not that of the other EP1-3 subtypes, increase in the DRG after complete Freund' adjuvant -induced peripheral inflammation. Administration of both an EP4 antagonist (AH23848, ((4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-Biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]- 4-heptenoic acid) and EP4 knockdown with intrathecally delivered short hairpin RNA (shRNA) attenuate inflammation-induced thermal and mechanical behavioral hypersensitivity, without changing basal pain sensitivity. AH23848 also reduces the PGE2 mediated sensitization of capsaicin-evoked currents in DRG neurons in vitro. These data suggest that EP4 is a potential target for the pharmacological treatment of inflammatory pain.


Key words: EP4 receptor, PGE2, dorsal root ganglion, inflammation, pain, peripheral sensitization


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