CCL2/CCR2参与神经病理性疼痛的多靶点作用机制

The Multi-target Mechanism of CCL2/CCR2 Involved in Neuropathic Pain

单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1,又称CCL2)是最早发现的人类CC族趋化因子,对单核细胞趋化作用强,激发炎症与免疫反应。CCL2及其受体CCR2(C-C chemokine receptor type 2)在疼痛发生和延续过程中扮演了重要角色。研究发现CCL2能够由神经元分泌,作为神经调质参与疼痛过程,是引发神经病理性疼痛、免疫和炎症反应的共同介质。CCL2在外周感觉传入神经、背根神经节、脊髓和延髓等不同水平参与神经病理性疼痛,易化痛觉传导。CCL2/CCR2的痛觉调节机制包括神经病理性疼痛:1增加瞬时态电压感受器阳离子通道,子类V,成员1(transient receptor potential cation channel,subfamily V,member 1,TRPV1)电流幅度和通过PI3K/Akt途径上调TRPV1的m RNA表达量;2 CCL2有可能激活PI3K/Akt信号通路选择性上调Nav1.8的m RNA表达量,增加河豚毒素(tetrodotoxin,TTX)不敏感钠通道的电流幅度;3明显降低背根神经节神经元电压依赖性非失活钾电流,对不同神经病理性疼痛模型大鼠背根神经节中钾通道的作用存有差异;4加强N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,AMPA)诱发的脊髓神经元内向电流,加强其自发性兴奋性突触后电流;5阿片受体与CCL2/CCR2之间存在双向调节机制;6 CCL2直接抑制神经元上的γ-氨基丁酸(γ-aminobutyric acid,GABA)电流。

CCL2 is the first discovered human CC chemokine and a potent chemotactic factor for monocytes,which induces immunological and inflammatory response. CCL2 and its receptor CCR2 play a key role in development and maintainence of neuropathic pain. Study found that CCL2 can be produced by neurons,and CCL2 acts as a neuromodulator in the process of pain disorder. CCL2 is the common mediator of neuropathic pain,immunological and inflammatory response. CCL2 involves in neuropathic pain at different levels,including peripheral sensory afferent nerve,dorsal root ganglia and spinal cord,which facilitates pain transmission. CCL2/CCR2regulates neuropathic painbased on the following mechanisms：①enhances current amplitude and levels of TRPV1mRNA by upregulating PI3K/Akt pathway,②CCL2 selectively increases mRNA of Nav1.8 through activating PI3K/Akt pathway and enhancing amplitude of TTX-R current,③significantly decreases voltage dependent non-inactivation potassium current（IK） in DRG neurons,and has different effects on potassium＆nbsp;channel in DRG neurons from different NP animal models,④enhances NMDA and AMPA evoked currents in spinal cord neurons,and enhances their spontaneous excitatory postsynaptic currents（EPSCs）,⑤there is a bidirectional regulation between opioid receptors and CCL2/CCR2,⑥CCL2 directly inhibits GABA current in neurons.