Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity.
Prostaglandin E(2) (PGE(2)) 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 PGE(2) 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 PGE(2)-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.
Lin
Chung-Ren
CR
Department of Anesthesiology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chung Gang University, Taiwan, Republic of China.
Amaya
Fumimasa
F
Barrett
Lee
L
Wang
Haibin
H
Takada
Junji
J
Samad
Tarek A
TA
Woolf
Clifford J
CJ
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000150:complications* / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010812:Physical Stimulation; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype
D001713:Biphenyl Compounds; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C046926:AH 23848; D015232:Dinoprostone; D002211:Capsaicin