Yao Yao, Tan Yong-Hui, Light Alan R, Mao Jianren, Yu Albert Cheung Hoi, Fu Kai-Yuan
Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China.
Department of Anesthesiology and Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah.
J Pain. 2016 Aug;17(8):889-903. doi: 10.1016/j.jpain.2016.03.008. Epub 2016 Apr 6.
Many derivatives of bisphosphonates, which are inhibitors of bone resorption, have been developed as promising agents for painful pathologies in patients with bone resorption-related diseases. The mechanism for pain relief by bisphosphonates remains uncertain. Studies have reported that bisphosphonates could reduce central neurochemical changes involved in the generation and maintenance of bone cancer pain. In this study, we hypothesized that bisphosphonates would inhibit spinal microglial activation and prevent the development of hyperalgesia caused by peripheral tissue injury. We investigated the effects of alendronate (a nitrogen-containing bisphosphonate) on the development of neuropathic pain and its role in modulating microglial activation in vivo and in vitro. Intrathecal and intraperitoneal administration of alendronate relieved neuropathic pain behaviors induced by chronic constriction sciatic nerve injury. Alendronate also significantly attenuated spinal microglial activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation without affecting astrocytes. In vitro, alendronate downregulated phosphorylated p38 and phosphorylated extracellular signal regulated kinase expression in lipopolysaccharide-stimulated primary microglia within 1 hour, and pretreatment with alendronate for 12 and 24 hours decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6). These findings indicate that alendronate could effectively relieve chronic constriction sciatic nerve injury-induced neuropathic pain by at least partially inhibiting the activation of spinal microglia and the p38 MAPK signaling pathway.
Alendronate could relieve neuropathic pain behaviors in animals by inhibiting the activation of spinal cord microglia and the p38 MAPK cell signaling pathway. Therapeutic applications of alendronate may be extended beyond bone metabolism-related disease.
双膦酸盐的许多衍生物是骨吸收抑制剂，已被开发为治疗骨吸收相关疾病患者疼痛性病症的有前景的药物。双膦酸盐缓解疼痛的机制仍不确定。研究报告称，双膦酸盐可减少参与骨癌疼痛产生和维持的中枢神经化学变化。在本研究中，我们假设双膦酸盐会抑制脊髓小胶质细胞活化，并预防由外周组织损伤引起的痛觉过敏的发展。我们研究了阿仑膦酸钠（一种含氮双膦酸盐）对神经性疼痛发展的影响及其在体内和体外调节小胶质细胞活化中的作用。鞘内和腹腔内给予阿仑膦酸钠可缓解慢性坐骨神经缩窄损伤诱导的神经性疼痛行为。阿仑膦酸钠还显著减弱了脊髓小胶质细胞活化和p38丝裂原活化蛋白激酶（MAPK）磷酸化，而不影响星形胶质细胞。在体外，阿仑膦酸钠在1小时内下调脂多糖刺激的原代小胶质细胞中磷酸化p38和磷酸化细胞外信号调节激酶的表达，并且用阿仑膦酸钠预处理12和24小时可降低炎性细胞因子（肿瘤坏死因子α、白细胞介素1β和6）的表达。这些发现表明，阿仑膦酸钠可通过至少部分抑制脊髓小胶质细胞活化和p38 MAPK信号通路有效缓解慢性坐骨神经缩窄损伤诱导的神经性疼痛。
阿仑膦酸钠可通过抑制脊髓小胶质细胞活化和p38 MAPK细胞信号通路缓解动物的神经性疼痛行为。阿仑膦酸钠的治疗应用可能会扩展到骨代谢相关疾病之外。
