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Abstract：
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.
摘要：
瘙痒是皮肤疾病的常见症状,但也可以伴随包括神经系统在内的其他组织的疾病。通过实验应用于皮肤的化学物质引起的急性瘙痒是通过伤害性神经元子集中的动作电位活动而引起和维持的。但是，在人类产生持续的瘙痒和伤害性感觉的病理条件下，这些瘙痒感觉神经元是否活跃或可能变得内在更容易兴奋，这在很大程度上是未知的。最近,确定了两种不同类型的皮肤伤害性背根神经节神经元对瘙痒化学物质有反应，并在瘙痒感觉中起作用。一个表达与mas相关的G偶联蛋白受体MRGPRA3，另一个表达MRGPRD（MRGPRA3和MRGPRD神经元，分别)。在这里，我们测试了这两种不同的瘙痒性伤害感受器在接触超敏反应发展后是否表现出增强的兴奋性，一种过敏性接触性皮炎的动物模型,人类常见的瘙痒性疾病。在这种疾病期间瘙痒感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瘙痒疾病或病理中活跃的相同类型的神经元有关。我们发现用半抗原挑战先前致敏小鼠的后爪或脸颊的小腿皮肤，方酸二丁酯,产生接触性超敏反应的症状，包括皮肤厚度增加和针对部位的自发性疼痛样（舔或擦拭）和瘙痒样（咬或抓挠）行为。MRGPRA3神经元的消融导致先前致敏小鼠颈部半抗原攻击的颈背的自发抓挠显着减少。在体内,电生理记录显示，与接受载体治疗的对照动物的神经元相比，神经支配半抗原攻击皮肤的MRGPRA3和MRGPRD神经元对机械和热刺激的反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，来自半抗原攻击小鼠的MRGPRA3+和MRGPRD+神经元均表现出明显更多的去极化静息膜电位，流变酶减少，与来自媒介物对照的神经元相比，在两倍的流变酶处的动作电位数量更多。这些神经元兴奋过度的迹象与河豚毒素敏感性和抗性钠电流的峰值幅度显着增加有关。因此，MRGPRA3+和MRGPRD+神经元的过度兴奋，部分是由钠电流增强引起的，可能导致伴随人类接触过敏和/或其他炎性疾病的自发性发痒和疼痛相关行为。
