School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, Texas, USA.
Department of Endodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, Texas, USA.
JCI Insight. 2020 Jun 4;5(11):137393. doi: 10.1172/jci.insight.137393.
Protease-activated receptor 2 (PAR2) has long been implicated in inflammatory and visceral pain, but the cellular basis of PAR2-evoked pain has not been delineated. Although PAR2-evoked pain has been attributed to sensory neuron expression, RNA-sequencing experiments show ambiguous F2rl1 mRNA detection. Moreover, many pharmacological tools for PAR2 are nonspecific, acting also on the Mas-related GPCR family (Mrg) that are highly enriched in sensory neurons. We sought to clarify the cellular basis of PAR2-evoked pain. We developed a PAR2-conditional knockout mouse and specifically deleted PAR2 in all sensory neurons using the PirtCre mouse line. Our behavioral findings show that PAR2 agonist-evoked mechanical hyperalgesia and facial grimacing, but not thermal hyperalgesia, are dependent on PAR2 expression in sensory neurons that project to the hind paw in male and female mice. F2rl1 mRNA is expressed in a discrete population (~4%) of mostly small-diameter sensory neurons that coexpress the Nppb and IL31ra genes. This cell population has been implicated in itch, but our work shows that PAR2 activation in these cells causes clear pain-related behaviors from the skin. Our findings show that a discrete population of DRG sensory neurons mediate PAR2-evoked pain.
蛋白酶激活受体 2（PAR2）长期以来一直被认为与炎症和内脏疼痛有关，但 PAR2 诱发疼痛的细胞基础尚未阐明。尽管 PAR2 诱发的疼痛归因于感觉神经元的表达，但 RNA 测序实验显示 F2rl1 mRNA 的检测结果并不明确。此外，许多用于 PAR2 的药理学工具是非特异性的，也作用于 Mas 相关 G 蛋白偶联受体家族（Mrg），该家族在感觉神经元中高度富集。我们试图阐明 PAR2 诱发疼痛的细胞基础。我们开发了一种 PAR2 条件性敲除小鼠，并使用 PirtCre 小鼠品系特异性地在所有感觉神经元中缺失 PAR2。我们的行为学研究结果表明，PAR2 激动剂诱发的机械性痛觉过敏和面部扭曲，但不引起热痛觉过敏，依赖于雄性和雌性小鼠中投射到后爪的感觉神经元中 PAR2 的表达。F2rl1 mRNA 表达在一小部分（约 4%）主要为小直径感觉神经元中，这些神经元共同表达 Nppb 和 Il31ra 基因。该细胞群与瘙痒有关，但我们的工作表明，这些细胞中 PAR2 的激活会引起皮肤相关的明显疼痛行为。我们的研究结果表明，DRG 感觉神经元中的一个离散细胞群介导了 PAR2 诱发的疼痛。
