Enhanced excitability of MRGPRA3-and MRGPRD-positive nociceptors in a model of inflammatory itch and pain
Enhanced excitability of MRGPRA3-and MRGPRD-positive nociceptors in a model of inflammatory itch and pain
复制标题
炎性瘙痒和疼痛模型中 MRGPRA3 和 MRGPRD 阳性伤害感受器的兴奋性增强
DOI：
10.1093/brain/awu007
复制
发表时间：
2014-04-01
期刊：
影响因子：
14.5
通讯作者：
LaMotte, Robert H.
中科院分区：
文献类型：
--
作者：
Qu, Lintao;Fan, Ni;LaMotte, Robert H.
Qu等人使用由过敏性接触性皮炎产生的炎性瘙痒和疼痛的动物模型，揭示了两种不同群体的刺激性皮肤伤害感受器的过度兴奋性，部分原因是钠电流增强。在人类过敏性疾病和炎症性疾病中，类似的机制可能导致自发性瘙痒和疼痛。瘙痒是皮肤疾病的常见症状，但也可能伴随其他组织（包括神经系统）的疾病。实验性应用于皮肤的化学品引起的急性瘙痒是由伤害感受神经元亚群中的动作电位活动引发和维持的。但是，在人类产生持续性瘙痒和伤害性感觉的病理条件下，这些疼痛感受神经元是否是活跃的，或者可能在本质上变得更易兴奋，这在很大程度上是未知的。最近，两种不同类型的皮肤伤害性背根神经节神经元被确定为对瘙痒化学物质做出反应并在瘙痒感觉中发挥作用。一个表达mas相关的G偶联蛋白受体MRGPRA 3，另一个表达MRGPRD（分别为MRGPRA 3（+）和MRGPRD（+）神经元）。在这里，我们测试了这两种不同的伤害感受器是否表现出增强的兴奋性后，发展的接触性超敏反应，过敏性接触性皮炎，一种常见的过敏性疾病在人类的动物模型。在这种病症期间，伤害感受神经元的兴奋性增加的特征也可能与在影响神经系统和其他组织或器官的其他神经炎疾病或病理中活跃的相同类型的神经元有关。我们发现，用半抗原方酸甘油酯（squaric acid chloroester）攻击先前致敏小鼠的后爪小腿或脸颊的皮肤，产生接触性超敏反应的症状，包括皮肤厚度增加和部位定向的自发性疼痛样（舔或擦拭）和瘙痒样（咬或抓）行为。去除MRGPRA 3（+）神经元导致先前致敏小鼠的半抗原激发的颈背的自发抓挠显著减少。在体内，电生理记录显示，与溶剂处理的对照动物的神经元相比，半抗原激发皮肤的MRGPRA 3（+）和MRGPRD（+）神经元对施加到其感受野的机械和热刺激的响应表现出更高的自发活动和/或异常后放电发生率。体外全细胞记录显示，与溶剂对照组的神经元相比，半抗原激发小鼠的MRGPRA 3（+）和MRGPRD（+）神经元均显示出显著更强的去极化静息膜电位、降低的基强度和更多的2倍基强度动作电位。神经元过度兴奋的这些迹象与河豚毒素敏感性和耐药性钠电流的峰值幅度显著增加有关。因此，部分由增强的钠电流引起的MRGPRA 3（+）和MRGPRD（+）神经元的过度兴奋性可能有助于伴随接触性超敏反应和/或人类其他炎症性疾病的自发性瘙痒和疼痛相关行为。
Using an animal model of inflammatory itch and pain produced by allergic contact dermatitis, Qu et al. reveal hyperexcitability in two distinct populations of pruriceptive cutaneous nociceptors, due in part to enhanced sodium currents. Similar mechanisms may contribute to spontaneous itch and pain in human allergic and inflammatory diseases.Itch is a common symptom of diseases of the skin but can also accompany diseases of other tissues including the nervous system. Acute itch from chemicals experimentally applied to the skin is initiated and maintained by action potential activity in a subset of nociceptive neurons. But whether these pruriceptive neurons are active or might become intrinsically more excitable under the pathological conditions that produce persistent itch and nociceptive sensations in humans is largely unexplored. Recently, two distinct types of cutaneous nociceptive dorsal root ganglion neurons were identified as responding to pruritic chemicals and playing a role in itch sensation. One expressed the mas-related G-coupled protein receptor MRGPRA3 and the other MRGPRD (MRGPRA3(+) and MRGPRD(+) neurons, respectively). Here we tested whether these two distinct pruriceptive nociceptors exhibited an enhanced excitability after the development of contact hypersensitivity, an animal model of allergic contact dermatitis, a common pruritic disorder in humans. The characteristics of increased excitability of pruriceptive neurons during this disorder may also pertain to the same types of neurons active in other pruritic diseases or pathologies that affect the nervous system and other tissues or organs. We found that challenging the skin of the calf of the hind paw or the cheek of previously sensitized mice with the hapten, squaric acid dibutyl ester, produced symptoms of contact hypersensitivity including an increase in skin thickness and site-directed spontaneous pain-like (licking or wiping) and itch-like (biting or scratching) behaviours. Ablation of MRGPRA3(+) neurons led to a significant reduction in spontaneous scratching of the hapten-challenged nape of the neck of previously sensitized mice. In vivo, electrophysiological recordings revealed that MRGPRA3(+) and MRGPRD(+) neurons innervating the hapten-challenged skin exhibited a greater incidence of spontaneous activity and/or abnormal after-discharges in response to mechanical and heat stimuli applied to their receptive fields compared with neurons from the vehicle-treated control animals. Whole-cell recordings in vitro showed that both MRGPRA3(+) and MRGPRD(+) neurons from hapten-challenged mice displayed a significantly more depolarized resting membrane potential, decreased rheobase, and greater number of action potentials at twice rheobase compared with neurons from vehicle controls. These signs of neuronal hyperexcitability were associated with a significant increase in the peak amplitude of tetrodotoxin-sensitive and resistant sodium currents. Thus, the hyperexcitability of MRGPRA3(+) and MRGPRD(+) neurons, brought about in part by enhanced sodium currents, may contribute to the spontaneous itch- and pain-related behaviours accompanying contact hypersensitivity and/or other inflammatory diseases in humans.