Li Xin, Jiang Siqing, Yang Hui, Liao Qian, Cao Shousong, Yan Xuebin, Huang Dong
Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South UniversityChangsha, China.
Department of Pharmacology, School of Pharmacy, Southwest Medical UniversityLuzhou, China.
Front Cell Neurosci. 2017 Jul 17;11:207. doi: 10.3389/fncel.2017.00207. eCollection 2017.
Breakthrough cancer pain (BTcP) is a high-intensity, short-duration, unpredictable and uncontrollable pain. Recent studies have shown that activation of gap junction (GJ) in spinal cord plays an important role in the pathogenesis of BTcP. We examined the expressions of Glial fibrillary acidic protein (GFAP), connexin (Cx) 43 protein and phosphorylation of Cx43 (p-Cx43) in the spinal cord of mice. In addition, we investigated the effects of Gap26, a selective GJ blocker, on the expressions of GFAP, Cx43 and p-Cx43 in BTcP mice. We found that the expressions of GFAP and Cx43 proteins were significantly upregulated while p-Cx43 was down-regulated in the spinal cord in a mouse model of BTcP. The overexpression of Cx43 protein in the spinal cord increased GJ formation and enhanced BTcP. The variation of the ratio of p-Cx43/T-Cx43 (total Cx43) affected the function of GJ to induce BTcP. Furthermore, BTcP was alleviated by Gap26 via reducing pain hypersensitivity. The inhibition of Cx43 and p-Cx43 by Gap26 attenuated BTcP but the p/T ratio of Cx43 remained unchanged in BTcP mice. We reveal that the expression and phosphorylation of Cx43 affected BTcP and GJ activation facilitated BTcP via a Cx43-mediated signaling in the spinal cord. The finding may provide a scientific rationale for discovery and development of novel therapeutic targets for the treatment of BTcP clinically.
爆发性癌痛（BTcP）是一种高强度、持续时间短、不可预测且难以控制的疼痛。最近的研究表明，脊髓中缝隙连接（GJ）的激活在BTcP的发病机制中起重要作用。我们检测了小鼠脊髓中胶质纤维酸性蛋白（GFAP）、连接蛋白（Cx）43蛋白的表达以及Cx43的磷酸化（p-Cx43）情况。此外，我们研究了选择性GJ阻滞剂Gap26对BTcP小鼠中GFAP、Cx43和p-Cx43表达的影响。我们发现，在BTcP小鼠模型中，脊髓中GFAP和Cx43蛋白的表达显著上调，而p-Cx43下调。脊髓中Cx43蛋白的过表达增加了GJ的形成并增强了BTcP。p-Cx43/T-Cx43（总Cx43）比值的变化影响了GJ诱导BTcP的功能。此外，Gap26通过降低疼痛超敏反应减轻了BTcP。Gap26对Cx43和p-Cx43的抑制减弱了BTcP，但在BTcP小鼠中Cx43的p/T比值保持不变。我们揭示，Cx43的表达和磷酸化影响了BTcP，并且GJ激活通过脊髓中Cx43介导的信号传导促进了BTcP。这一发现可能为临床上发现和开发治疗BTcP的新型治疗靶点提供科学依据。
