激活外周A类传入纤维缓解大鼠神经病理性疼痛的机制研究

Neuropathic pain is often hard to treat clinically, and the underlying mechanisms are obscure. Gate control theory proposed the presence of the presynaptic inhibition of the A-fibers to C-fibers, although controversial, TENS (transdermal electrical nerve stimulation) , the treatment method based on it, has analgesic efficacy. Preliminary studies indicated that selectively injury to A-type input fibers may induce neuropathic pain. Based on the work above, the proposed project will use in-vivo electrophysiology record method, pain behavioral tests and peripheral inflammatory tests in two animal models of neuropathic pain: the Chronic Compression Injury (CCI) and Cobra-venom induced Rapid Demyelination (CRD) models to different branches of sciatic nerve innervating muscles or the skin on the leg. We will observe the thermal, tactile and cold allodynia, the hyperexcitability of C-fiber and neurogenic inflammation of the affected skin, and analyze the relationship between selective activating of A input fibers innervating different tissues and neuropathic pain. Furthermore, we will try to alleviate the neuropathic pain via selectively activating A-fiber inputs of deep tissues or skin in multiple models of chronic pain including CCI, CRD and the chronic compression of dorsal root ganglion (CCD), and record changes in C-fiber abnormal activities and pain-related behaviors. This study may provide potentially novel strategies for the mechanism study and treatment of neuropathic pain，and to lay the foundation for further research.

神经病理性疼痛的机制尚未阐明，至今没有找到确切有效的治疗方法。闸门控制学说提出粗纤维对细纤维存在突触前抑制，尽管有争议，但由此发展而来的透皮电刺激等治疗在临床上有镇痛疗效。申请人参与的前期研究提示，A纤维的选择性损伤在神经病理性痛的发生中起重要的作用。本项目拟在上述基础上，在大鼠支配肌肉和支配皮肤的神经分别建立选择性慢性压迫损伤(CCI)模型和急性脱髓鞘(CRD)模型，进行行为学测试、神经电生理记录和外周神经源性炎症反应测定，观察疼痛阈值、C纤维放电和皮肤炎症反应，分析外周深部组织和皮肤来源的A类传入纤维的选择性损伤与神经病理性疼痛的关系。并将在CCI，CRD和慢性背根神经节压迫(CCD)病理性疼痛动物模型上对支配肌肉或皮肤的神经近端予电刺激，观察C纤维放电的改变，以探讨不同组织来源A纤维兴奋性补偿的镇痛效果。本课题将为神经病理性痛的机制研究和治疗提供新的思路,并为进⼀步深入研究打下基础。

神经病理性疼痛是临床上常见的一类难治且顽固的疾病，严重影响患者生活质量。据估计，中国有大约近亿神经病理性疼痛患者。然而关于神经病理性疼痛的外周机制尚未阐明。本研究主要运用大鼠在体DRG电生理记录结合行为学、Evans blue渗出等手段对外周的A纤维传入在神经病理性疼痛中的作用展开了系统性的研究，并进一步在背根神经节（DRG）层面对A纤维传入及伤害性C纤维传入的相互调控作了探究。研究发现，正常外周A纤维传入对大鼠伤害性疼痛信息传入有抑制作用，缺失A纤维传入活动后，大鼠产生C伤害性神经元的敏化，外周神经源性炎症，以及一系列的神经病理性疼痛行为；进一步明确了在特异缺失来源于肌肉等深部组织（非皮肤）的A纤维传入活动后极短时间内（10min）就可导致神经病理性疼痛，且持续数周时间；皮肤来源的C纤维活动对肌肉等深部组织的疼痛有抑制作用；这种抑制作用依赖于完整的皮肤神经支配，完整的背根反射环路以及只在相同或是相邻脊髓节段支配的皮节上发挥作用。该研究一定程度上阐明了外周A纤维传入在神经病理性疼痛中的作用，明确了体表C纤维传入对肌肉痛的调节作用。为体表电刺激疗法，以及体表涂抹药剂疗法提供了坚实的实验依据，并为进一步研究神经病理性疼痛的外周机制提供了思路。