Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation
Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation
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DOI：
10.1073/pnas.1300820110
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发表时间：
2013-08-13
影响因子：
11.1
通讯作者：
Schaible, Hans-Georg
中科院分区：
文献类型：
--
作者：
Natura, Gabriel;Baer, Karl-Juergen;Schaible, Hans-Georg
疼痛介质前列腺素E-2（PGE（2））通过EP 2和EP 4受体使伤害感受通路敏感，EP 2和EP 4受体与G（s）蛋白偶联并增加cAMP。然而，PGE（2）也激活EP 3受体，并且EP 3受体剪接变体的主要信号传导途径通过G（i）蛋白抑制cAMP合成。这种相反的效应提出了一个有趣的问题，即G（i）蛋白偶联的EP 3受体是否可以抵消EP 2和EP 4受体介导的PGE的原伤害效应（2）。我们发现EP 3受体在初级感觉神经元和脊髓中广泛定位。在健康动物中，在这些部位选择性激活EP 3受体不会使伤害感受神经元敏感。与此相反，它产生深刻的镇痛和减少反应的外周和脊髓伤害性神经元的伤害性刺激，但只有当关节发炎。在分离的背根神经节神经元中，EP 3受体激活抵消了PGE的增敏作用（2），兴奋性EP受体的刺激促进了膜相关抑制性EP 3受体的表达。因此，我们建议，EP 3受体提供内源性疼痛控制和EP 3受体的选择性激活可能是一种独特的方法来逆转炎症性疼痛。重要的是，我们确定了疼痛性骨关节炎患者关节神经中的EP 3受体。
The pain mediator prostaglandin E-2 (PGE(2)) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to G(s) proteins and increase cAMP. However, PGE(2) also activates EP3 receptors, and the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via G(i) proteins. This opposite effect raises the intriguing question of whether the G(i)-protein-coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE(2). 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 PGE(2), 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.