Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity
Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity
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DOI：
10.1124/jpet.106.105569
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Woolf, Clifford J.
中科院分区：
文献类型：
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作者：
Lin, Chung-Ren;Amaya, Fumimasa;Woolf, Clifford J.
前列腺素E-2(PGE(2))既是组织炎症部位释放的炎症介质，又是改变神经元兴奋性和突触处理的神经调节剂。PGE(2)的作用是由四个G蛋白偶联的EP受体(EP1-EP4)介导的。在这里，我们发现EP4受体亚型是由初级感觉背根神经节(DRG)神经元的一个子集表达的，并且在完全弗氏佐剂诱导的外周炎症后，EP4受体亚型的水平增加，而不是其他EP1-3亚型的水平。鞘内注射EP4拮抗剂[AH23848，(4Z)-7-[(Rel-1S，2S，5R)-5-((1，1‘-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3oxocyclopentyl]-4-heptenoic酸]和EP4基因敲除)可减轻炎症诱导的热和机械行为超敏反应，但不改变基础痛敏。AH23848还可降低PGE(2)对体外培养的DRG神经元辣椒素诱发电流的敏化作用。这些数据表明EP4是炎性疼痛药物治疗的潜在靶点。
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)-3oxocyclopentyl]-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.