Department of Anesthesia, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
Department of Anesthesia, People's Hospital of Hunan Province, Changsha, Hunan 410005, P.R. China.
Int J Mol Med. 2018 Dec;42(6):3209-3219. doi: 10.3892/ijmm.2018.3878. Epub 2018 Sep 13.
Recently, α2-adrenoceptors (α2-AR) agonists have been shown to have anti-nociceptive effects and thus may become a promising therapeutic strategy for neuropathic pain. tizanidine is a highly selective α2-AR agonist, but the effect mechanism of tizanidine in neuropathic pain remains largely unknown. The present study investigated whether tizanidine has anti-nociceptive effects in spared nerve injury (SNI) model of neuropathic pain in rats, as well as explored the underlying molecular mechanism. We found that the rats in SNI group showed significantly higher mechanical and thermal hyperalgesia, accompanied with increased production of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), as well as the activation of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling. PDTC, an inhibitor of TLR4/NF-κB signaling, could significantly attenuate the SNI-induced mechanical and thermal hyperalgesia and the production of proinflammatory cytokines. Moreover, treatment with tizanidine also attenuated the SNI-induced mechanical and thermal hyperalgesia, suppressed production of the proinflammatory cytokines, and inhibited the activation of TLR4/NF-κB pathway, which could be reversed by pretreatment with BRL44408, a selective α2-AR antagonist. Taken these findings together, we demonstrated that tizanidine has anti-nociceptive effects on neuropathic pain via inhibiting the production of proinflammatory cytokines through suppressing the activation of TLR4/NF-κB p65 signaling pathway.
最近，α2-肾上腺素能受体（α2-AR）激动剂已被证明具有抗伤害感受作用，因此可能成为治疗神经性疼痛的有前途的治疗策略。替扎尼定是一种高度选择性的α2-AR 激动剂，但替扎尼定在神经性疼痛中的作用机制在很大程度上仍不清楚。本研究探讨了替扎尼定是否对神经病理性疼痛的 spared nerve injury（SNI）模型大鼠具有抗伤害感受作用，并探讨了其潜在的分子机制。我们发现，SNI 组大鼠表现出明显的机械性和热痛觉过敏，伴随着促炎细胞因子（包括白细胞介素 1β（IL-1β）、IL-6 和肿瘤坏死因子-α（TNF-α））的产生增加，以及 Toll 样受体 4（TLR4）/核因子-κB（NF-κB）信号通路的激活。TLR4/NF-κB 信号通路的抑制剂 PDTC 可显著减轻 SNI 引起的机械性和热痛觉过敏以及促炎细胞因子的产生。此外，替扎尼定治疗也减轻了 SNI 引起的机械性和热痛觉过敏，抑制了促炎细胞因子的产生，并抑制了 TLR4/NF-κB 途径的激活，这可以通过预先用选择性 α2-AR 拮抗剂 BRL44408 逆转。综上所述，我们证明替扎尼定通过抑制 TLR4/NF-κB p65 信号通路的激活抑制促炎细胞因子的产生，对神经性疼痛具有抗伤害感受作用。
