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NEUROPHARMACOLOGY

Prostaglandin E₂ Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity

Neural Plasticity Research Group, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (F.A., L.B., H.W., T.A.S., C.J.W.); Pfizer Global Research and Development, Discovery Biology Research, Aichi, Japan (J.T.); and Department of Anesthesiology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chung Gang University, Taiwan, Republic of China (C.-R.L.)

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 attenuates 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.

Address correspondence to: Dr. Clifford J. Woolf, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 149 13th Street, Room 4309, Charlestown, MA 02129. E-mail: cjwoolf{at}partners.org

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