Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Pain. 2022 Mar 1;163(3):445-460. doi: 10.1097/j.pain.0000000000002363.
Lysophosphatidic acid (LPA) is involved in the pathophysiology of cholestatic pruritus and neuropathic pain. Slowly conducting peripheral afferent C-nerve fibers are crucial in the sensations of itch and pain. In animal studies, specialized neurons ("pruriceptors") have been described, expressing specific receptors, eg, from the Mas-related G-protein-coupled receptor family. Human nerve fibers involved in pain signaling ("nociceptors") can elicit itch if activated by focalized stimuli such as cowhage spicules. In this study, we scrutinized the effects of LPA in humans by 2 different application modes on the level of psychophysics and single nerve fiber recordings (microneurography). In healthy human subjects, intracutaneous LPA microinjections elicited burning pain, whereas LPA application through inactivated cowhage spicules evoked a moderate itch sensation. Lysophosphatidic acid microinjections induced heat hyperalgesia and hypersensitivity to higher electrical stimulus frequencies. Pharmacological blockade of transient receptor potential channel A1 or transient receptor potential channel vanilloid 1 reduced heat hyperalgesia, but not acute chemical pain. Microneurography revealed an application mode-dependent differential activation of mechanosensitive (CM) and mechanoinsensitive C (CMi) fibers. Lysophosphatidic acid microinjections activated a greater proportion of CMi fibers and more strongly than CM fibers; spicule application of LPA activated CM and CMi fibers to a similar extent but excited CM fibers more and CMi fibers less intensely than microinjections. In conclusion, we show for the first time in humans that LPA can cause pain as well as itch dependent on the mode of application and activates afferent human C fibers. Itch may arise from focal activation of few nerve fibers with distinct spatial contrast to unexcited surrounding afferents and a specific combination of activated fiber subclasses might contribute.
溶血磷脂酸（LPA）参与胆汁淤积性瘙痒和神经病理性疼痛的病理生理学。缓慢传导的周围传入 C 神经纤维在瘙痒和疼痛感觉中起着至关重要的作用。在动物研究中，已经描述了表达特定受体的专门神经元（“瘙痒感受器”），例如 Mas 相关 G 蛋白偶联受体家族。参与疼痛信号传导的人类神经纤维（“伤害感受器”）如果被牛痘刺的局灶性刺激激活，也可以引起瘙痒。在这项研究中，我们通过两种不同的应用模式（心理物理学和单纤维记录（微神经记录））在人体上仔细研究了 LPA 的作用。在健康的人类受试者中，皮内 LPA 微注射引起灼热痛，而通过失活的牛痘刺的 LPA 应用引起中度瘙痒感。溶血磷脂酸微注射诱导热痛觉过敏和对更高电刺激频率的敏感性。瞬时受体电位通道 A1 或瞬时受体电位通道香草素 1 的药理学阻断减少了热痛觉过敏，但不减少急性化学疼痛。微神经记录显示，应用模式依赖性地激活机械敏感（CM）和机械不敏感 C（CMi）纤维。LPA 微注射激活 CMi 纤维的比例大于 CM 纤维，并且比 CM 纤维更强；LPA 的刺应用激活 CM 和 CMi 纤维的程度相似，但比微注射更强烈地激活 CM 纤维，更弱地激活 CMi 纤维。总之，我们首次在人类中证明，LPA 可以根据应用模式引起疼痛和瘙痒，并激活传入的人类 C 纤维。瘙痒可能是由于少数神经纤维的局灶性激活引起的，与未兴奋的周围传入纤维具有明显的空间对比，并且特定的激活纤维亚类组合可能有助于瘙痒的产生。
