Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
Department of Microbiology, Immunology, Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
Sci Rep. 2017 Feb 14;7:42550. doi: 10.1038/srep42550.
Neuropathic pain symptoms respond poorly to available therapeutics, with most treated patients reporting unrelieved pain and significant impairment in daily life. Here, we show that Pannexin 1 (Panx1) in hematopoietic cells is required for pain-like responses following nerve injury in mice, and a potential therapeutic target. Panx1 knockout mice (Panx1) were protected from hypersensitivity in two sciatic nerve injury models. Bone marrow transplantation studies show that expression of functional Panx1 in hematopoietic cells is necessary for mechanical hypersensitivity following nerve injury. Reconstitution of irradiated Panx1 knockout mice with hematopoietic Panx1 cells engineered to re-express Panx1 was sufficient to recover hypersensitivity after nerve injury; this rescue required expression of a Panx1 variant that can be activated by G protein-coupled receptors (GPCRs). Finally, chemically distinct Panx1 inhibitors blocked development of nerve injury-induced hypersensitivity and partially relieved this hypersensitivity after it was established. These studies indicate that Panx1 expressed in immune cells is critical for pain-like effects following nerve injury in mice, perhaps via a GPCR-mediated activation mechanism, and suggest that inhibition of Panx1 may be useful in treating neuropathic pain.
神经病理性疼痛症状对现有疗法反应不佳，大多数接受治疗的患者报告疼痛未缓解，日常生活受到严重影响。在这里，我们表明，在小鼠神经损伤后，造血细胞中的连接蛋白 1（Panx1）对于疼痛样反应是必需的，并且是一个潜在的治疗靶点。Panx1 敲除小鼠（Panx1）在两种坐骨神经损伤模型中均受到保护，不会产生过敏反应。骨髓移植研究表明，在神经损伤后，造血细胞中功能性 Panx1 的表达对于机械性过敏反应是必需的。用工程化重新表达 Panx1 的造血 Panx1 细胞重建照射的 Panx1 敲除小鼠足以在神经损伤后恢复过敏反应；这种挽救需要表达一种可以被 G 蛋白偶联受体（GPCR）激活的 Panx1 变体。最后，化学上不同的 Panx1 抑制剂阻断了神经损伤诱导的过敏反应的发展，并在其建立后部分缓解了这种过敏反应。这些研究表明，免疫细胞中表达的 Panx1 对于小鼠神经损伤后的疼痛样效应至关重要，可能通过 GPCR 介导的激活机制，并且表明抑制 Panx1 可能有助于治疗神经病理性疼痛。
