See Lily P, Sripinun Puttipong, Lu Wennan, Li Jiaqi, Alboloushi Naela, Alvarez-Periel Elena, Lee Su-Min, Karabucak Bekir, Wang Steven, Jordan-Sciutto Kelly L, Theken Katherine N, Mitchell Claire H
Departments of Basic and Translational Science, University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Endodontics, University of Pennsylvania, Philadelphia, Pennsylvania.
Departments of Basic and Translational Science, University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Orthodontics, University of Pennsylvania, Philadelphia, Pennsylvania.
J Pain. 2024 Apr;25(4):1039-1058. doi: 10.1016/j.jpain.2023.10.026. Epub 2023 Nov 11.
An enhanced understanding of neurotransmitter systems contributing to pain transmission aids in drug development, while the identification of biological variables like age and sex helps in the development of personalized pain management and effective clinical trial design. This study identified enhanced expression of purinergic signaling components specifically in painful inflammation, with levels increased more in women as compared to men. Inflammatory dental pain is common and potentially debilitating; as inflammation of the dental pulp can occur with or without pain, it provides a powerful model to examine distinct pain pathways in humans. In control tissues, P2X3 and P2X2 receptors colocalized with PGP9.5-positive nerves. Expression of the ecto-nucleotidase NTPDase1 (CD39) increased with exposure to extracellular adenosine triphosphate (ATP), implying CD39 acted as a marker for sustained elevation of extracellular ATP. Both immunohistochemistry and immunoblots showed P2X2, P2X3, and CD39 increased in symptomatic pulpitis, suggesting receptors and the ATP agonist were elevated in patients with increased pain. The increased expression of P2X3 and CD39 was more frequently observed in women than men. In summary, this study identifies CD39 as a marker for chronic elevation of extracellular ATP in fixed human tissue. It supports a role for increased purinergic signaling in humans with inflammatory dental pain and suggests the contribution of purines shows sexual dimorphism. This highlights the potential for P2X antagonists to treat pain in humans and stresses the need to consider sex in clinical trials that target pain and purinergic pathways. PERSPECTIVE: This article demonstrates an elevation of ATP-marker CD39 and of ATP receptors P2X2 and P2X3 with inflammatory pain and suggests the rise is greater in women. This highlights the potential for P2X antagonists to treat pain and stresses the consideration of sexual dimorphism in studies of purines and pain.
对参与疼痛传递的神经递质系统的深入了解有助于药物研发，而识别年龄和性别等生物学变量则有助于个性化疼痛管理的发展以及有效的临床试验设计。本研究发现嘌呤能信号传导成分在疼痛性炎症中表达增强，女性的表达水平比男性增加得更多。炎性牙痛很常见且可能使人衰弱；由于牙髓炎症可伴有或不伴有疼痛，它为研究人类不同的疼痛途径提供了一个有力的模型。在对照组织中，P2X3和P2X2受体与PGP9.5阳性神经共定位。外核苷酸酶NTPDase1（CD39）的表达随着细胞外三磷酸腺苷（ATP）的暴露而增加，这意味着CD39可作为细胞外ATP持续升高的标志物。免疫组织化学和免疫印迹均显示，有症状的牙髓炎中P2X2、P2X3和CD39增加，表明疼痛增加的患者中受体和ATP激动剂升高。P2X3和CD39表达增加在女性中比男性更常见。总之，本研究确定CD39为固定人体组织中细胞外ATP慢性升高的标志物。它支持嘌呤能信号传导增加在患有炎性牙痛的人类中的作用，并表明嘌呤的作用存在性别差异。这突出了P2X拮抗剂治疗人类疼痛的潜力，并强调在针对疼痛和嘌呤能途径的临床试验中需要考虑性别因素。观点：本文证明了ATP标志物CD39以及ATP受体P2X2和P2X3在炎性疼痛时升高，并表明女性升高幅度更大。这突出了P2X拮抗剂治疗疼痛的潜力，并强调在嘌呤与疼痛的研究中考虑性别差异。
