Wang Chunmei, Xue Yaping, Lu Qiuhua, Shi Yonghui, Tang Wei, Wang Dongmei
Provincial Key Laboratory of Developmental Biology and Neuroscience, College of Life Sciences, Fujian Normal University, 350117 Fuzhou, Fujian, China.
Front Biosci (Landmark Ed). 2022 Jul 13;27(7):220. doi: 10.31083/j.fbl2707220.
The characterization of neuropathic pain is maladaptive plasticity within the nociceptive system. Multiple alterations contribute to complex pain phenotypes. Adrenomedullin (AM) has been documented to be a pain mediator. However, its involvement in pathological pain is poorly understood. We studied the contribution of AM to chronic neuropathic pain in the spinal nerve ligation (SNL) model.
Daily injection of the AM receptor antagonist AM22-52 (10 nmol) via an intrathecal (i.t.) route after SNL inhibited mechanical allodynia starting on day 6. Single administration of AM22-52 produced an immediate attenuation on pain hypersensitivity on day 2 or 10 post-SNL. Protein and mRNA levels were assayed by immunofluorescent staining and qRT-PCR, respectively, on days 1, 3, 7 and 15 post-SNL.
The results showed that AM at both protein and mRNA levels was increased in both injured (L5) and adjacent uninjured (L4) nerves starting on day 3 post-SNL. In dorsal root ganglion (DRG) at L5, AM was increase on days 1-7 at mRNA level but only on day 7 at protein level. However, AM was increase at mRNA level on days 1-7 and at protein level on days 3-15 in L4 DRG. AM mRNA expression was upregulated on days 1-7 in the spinal cord. Expression of receptor activity-modifying protein 2 (RAMP2), an essential AM1 receptor component, was upregulated in small and medium-diameter neurons on days 1-15 in both L5 and L4 DRG. Furthermore, single administration of AM22-52 suppressed the increase of nNOS in DRG induced by SNL and daily injection of AM22-52 for 7 days inhibited SNL-induced increase of CGRP mRNA in the spinal dorsal horn.
This study indicates that the increased AM bioactivity in injured and uninjured peripheral nerves, uninjured adjacent DRG and the spinal dorsal horn play a critical role mainly in the late-phase development of neuropathic pain. The mechanism may involve the recruitment of nNOS and CGRP.
神经性疼痛的特征是伤害性感受系统内的适应性不良可塑性。多种改变导致复杂的疼痛表型。肾上腺髓质素（AM）已被证明是一种疼痛介质。然而，其在病理性疼痛中的作用尚不清楚。我们在脊神经结扎（SNL）模型中研究了AM对慢性神经性疼痛的作用。
SNL后每天经鞘内（i.t.）途径注射AM受体拮抗剂AM22-52（10 nmol），从第6天开始抑制机械性异常性疼痛。单次给予AM22-52可在SNL后第2天或第10天立即减轻疼痛超敏反应。分别在SNL后第1、3、7和15天通过免疫荧光染色和qRT-PCR检测蛋白和mRNA水平。
结果显示，从SNL后第3天开始，在受伤（L5）和相邻未受伤（L4）神经中，AM的蛋白和mRNA水平均升高。在L5背根神经节（DRG）中，AM在mRNA水平上在第1-7天升高，但在蛋白水平上仅在第7天升高。然而，在L4 DRG中，AM在mRNA水平上在第1-7天升高，在蛋白水平上在第3-15天升高。脊髓中AM mRNA表达在第1-7天上调。受体活性修饰蛋白2（RAMP2）是AM1受体的重要组成部分，在L5和L4 DRG的中小直径神经元中，其表达在第1-15天上调。此外，单次给予AM22-52可抑制SNL诱导的DRG中nNOS的增加，每天注射AM22-52 7天可抑制SNL诱导的脊髓背角CGRP mRNA的增加。
本研究表明，受伤和未受伤的外周神经、未受伤的相邻DRG和脊髓背角中AM生物活性的增加主要在神经性疼痛的后期发展中起关键作用。其机制可能涉及nNOS和CGRP的募集。
