Department of Neurology & Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China.
Laboratory of Molecular Pharmacology and Drug Discovery, Institute of Chinese Materia Medica, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China.
ACS Chem Neurosci. 2023 Jul 19;14(14):2548-2559. doi: 10.1021/acschemneuro.3c00217. Epub 2023 Jun 28.
Central post-stroke pain (CPSP) is a neuropathic pain syndrome that frequently occurs following cerebral stroke. The pathogenesis of CPSP is mainly due to thalamic injury caused by ischemia and hemorrhage. However, its underlying mechanism is far from clear. In the present study, a thalamic hemorrhage (TH) model was established in young male mice by microinjection of 0.075 U of type IV collagenase into the unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus. We found that TH led to microglial pannexin (Panx)-1, a large-pore ion channel, opening within the thalamus accompanied with thalamic tissue injury, pain sensitivities, and neurological deficit, which were significantly prevented by either intraperitoneal injection of the Panx1 blocker carbenoxolone or intracerebroventricular perfusion of the inhibitory mimetic peptide 10Panx. However, inhibition of Panx1 has no additive effect on pain sensitivities upon pharmacological depletion of microglia. Mechanistically, we found that carbenoxolone alleviated TH-induced proinflammatory factors transcription, neuronal apoptosis, and neurite disassembly within the thalamus. In summary, we conclude that blocking of microglial Panx1 channels alleviates CPSP and neurological deficit through, at least in part, reducing neural damage mediated by the inflammatory response of thalamic microglia after TH. Targeting Panx1 might be a potential strategy in the treatment of CPSP.
中枢性卒中后疼痛（CPSP）是一种常见于脑卒中后的神经性疼痛综合征。CPSP 的发病机制主要是由于缺血和出血引起的丘脑损伤。然而，其潜在的机制尚不清楚。在本研究中，通过向雄性幼鼠单侧丘脑腹后外侧核和腹后内侧核微注射 0.075U Ⅳ型胶原酶，建立了丘脑出血（TH）模型。我们发现，TH 导致丘脑内小胶质细胞 Panx-1（一种大孔离子通道）开放，伴有丘脑组织损伤、痛觉敏化和神经功能缺损，这些损伤可被腹腔内注射 Panx1 阻滞剂 carbenoxolone 或脑室内灌注抑制性模拟肽 10Panx 显著预防。然而，在药理学耗尽小胶质细胞后，抑制 Panx1 对痛觉敏化没有附加作用。在机制上，我们发现 carbenoxolone 减轻了 TH 诱导的促炎因子转录、神经元凋亡和 thalamic 内神经纤维解体。总之，我们得出结论，阻断小胶质细胞 Panx1 通道通过减轻 TH 后丘脑小胶质细胞炎症反应介导的神经损伤，至少部分缓解 CPSP 和神经功能缺损。靶向 Panx1 可能是治疗 CPSP 的一种潜在策略。
