Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada; Department of Psychiatry, McGill University, Montréal, Québec H4H 1R3, Canada.
Exp Neurol. 2014 Nov;261:354-66. doi: 10.1016/j.expneurol.2014.05.028. Epub 2014 Jun 5.
Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor sensitization. Blocking COX2/PGE2/EP4 signaling at an earlier stage of inflammation or injury is crucial for preventing the transition from acute pain to a chronic state.
前列腺素 E2（PGE2）是一种在炎症组织中丰富的已知疼痛介质，在炎症性和神经性疼痛等慢性疼痛状况的发生中起着关键作用。PGE2 对伤害性感觉背根神经节（DRG）神经元（伤害感受器）的长期敏感化可能导致从急性疼痛向慢性疼痛的转变。然而，其潜在的细胞机制尚不清楚。在这项研究中，我们检验了这样一个假设，即促进 EP 受体的合成和顺行轴突运输有助于 PGE2 延长伤害感受器的敏感化。以剂量和时间依赖性方式向足底（i.pl.）注射稳定的 PGE2 类似物 16,16-二甲基 PGE2（dmPGE2），不仅引起了持续 1 天的原发性触觉过敏，而且还延长了随后 i.pl.注射 dmPGE2 引起的触觉过敏，从 1 天延长至 4 天。此外，随着多次顺序 i.pl.注射 dmPGE2，触觉过敏的持续时间逐渐延长。选择性 EP1 或 EP4 受体拮抗剂、cAMP、PKA、PKC、PKCε 或 PLC 的抑制剂以及白细胞介素-6（IL-6）中和抗血清的共注射，不同程度地阻断了由第 1 次 dmPGE2 引起的原发性触觉过敏和由第 2 次 dmPGE2 引起的触觉过敏，提示这些信号事件参与了 dmPGE2 诱导的伤害感受器激活和敏感化。选择性 COX2 抑制剂或两种 EP4 拮抗剂的共注射可预防或缩短致炎剂延长的伤害感受器敏感化。向 L4-6 DRG 神经元和周围神经中 i.pl.注射 dmPGE2 或角叉菜胶会随时间增加 EP4 水平。EP4 表达于 L4-6 DRG 中约一半的 IB4 结合伤害感受器中。总之，我们的数据表明，刺激合成和顺行轴突运输以增加伤害感受器轴突末端的 EP4 可用性可能是 PGE2 延长伤害感受器敏感化的一种新机制。在炎症或损伤的早期阶段阻断 COX2/PGE2/EP4 信号对于防止急性疼痛向慢性状态的转变至关重要。
