Sun Chengkuan, Wu Guangzhi, Zhang Zhan, Cao Rangjuan, Cui Shusen
Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Front Mol Neurosci. 2022 Apr 14;15:859166. doi: 10.3389/fnmol.2022.859166. eCollection 2022.
Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.
神经性疼痛通常由躯体感觉系统的损伤或功能障碍引起，药物治疗是常见的治疗方式。目前，仍没有令人满意的药物，如阿片类药物和利多卡因，它们具有很高的成瘾风险。蛋白酪氨酸磷酸酶受体D型（PTPRD）是成瘾途径中已知的治疗靶点，针对它的小分子抑制剂，如7-丁氧基鬼臼毒素类似物（7-BIA），最近已被开发用于解决成瘾问题。在神经性疼痛大鼠模型中，背根神经节（DRG）中的PTPRD也上调，但尚不清楚PTPRD是否促成神经性疼痛的发展。在此，我们建立了慢性缩窄损伤（CCI）模型，并评估了PTPRD的表达及其与神经性疼痛的关联。我们发现，CCI后DRG中PTPRD的表达逐渐增加，其表达与通过机械和热刺激评估的超敏反应的逐渐发展相伴。PTPRD基因敲低和给予PTPRD抑制剂7-BIA均减轻了CCI诱导的神经性疼痛，同时上调了DRG中的STING和IFN-α。用STING抑制剂H-151治疗消除了PTPRD基因敲低的镇痛作用。综上所述，我们的研究表明，CCI后DRG中PTPRD水平升高通过STING-IFN-I途径参与神经性疼痛的发展。7-BIA是一种具有抗成瘾作用的PTPRD小分子抑制剂，可能代表一种新型且安全的治疗策略，用于神经性疼痛的临床管理，而无成瘾风险。
