Neuroscience Department, Merck & Co., Inc., West Point, PA, USA.
Neurotherapeutics. 2020 Jul;17(3):826-838. doi: 10.1007/s13311-020-00934-2. Epub 2020 Oct 2.
Current therapies for the treatment of chronic pain provide inadequate relief for millions of suffering patients, demonstrating the need for better therapies that will treat pain effectively and improve the quality of patient's lives. Better understanding of the mechanisms that mediate chronic pain is critical for developing drugs with improved clinical outcomes. Adenosine triphosphate (ATP) is a key modulator in nociceptive pathways. Release of ATP from injured tissue or sympathetic efferents has sensitizing effects on sensory neurons in the periphery, and presynaptic vesicular release of ATP from the central terminals can increase glutamate release thereby potentiating downstream central sensitization mechanisms, a condition thought to underlie many chronic pain conditions. The purinergic receptors on sensory nerves primarily responsible for ATP signaling are P2X3 and P2X2/3. Selective knockdown experiments, or inhibition with small molecules, demonstrate P2X3-containing receptors are key targets to modulate nociceptive signals. Preclinical studies have identified that P2X3-containing receptors are critical for sensory transduction for bladder function, and clinical studies have shown promise in treatment for bladder pain and pain associated with osteoarthritis. Further clinical characterization of antagonists to P2X3-containing receptors may lead to improved therapies in the treatment of chronic pain.
目前用于治疗慢性疼痛的疗法为数百万疼痛患者提供的缓解效果不足，这表明需要更好的疗法，以有效治疗疼痛并改善患者的生活质量。更好地了解介导慢性疼痛的机制对于开发具有改善临床效果的药物至关重要。三磷酸腺苷（ATP）是伤害感受途径中的关键调节剂。来自损伤组织或交感传出神经的 ATP 释放对周围感觉神经元具有致敏作用，而来自中枢末端的 ATP 囊泡释放可增加谷氨酸释放，从而增强下游的中枢敏化机制，这种情况被认为是许多慢性疼痛状况的基础。感觉神经上主要负责 ATP 信号的嘌呤能受体是 P2X3 和 P2X2/3。选择性敲低实验或小分子抑制表明，含有 P2X3 的受体是调节伤害性信号的关键靶点。临床前研究已经确定 P2X3 受体在膀胱功能的感觉转导中至关重要，并且临床研究表明在治疗膀胱疼痛和与骨关节炎相关的疼痛方面具有潜力。对 P2X3 受体拮抗剂的进一步临床特征分析可能会导致改善慢性疼痛治疗的疗法。
