基于脊髓背角TRPV1磷酸化调节机制的电针干预神经病理痛研究

Neuropathic pain is a common but refractory disease, and its pathological mechanism is complicated. The central sensitization is one of the key mechanisms of neuropathic pain. TRPV1 plays an important role in its central sensitization. However, the pathways of TRPV1 in the central sensitization in the induction and maintenance of neuropathic pain remain unknown. Rat model of spared nerve injury (SNI) neuropathic pain is made in the study, cAMP/PKA, PKC, p-TRPV1 function sensitization pathway, as well as sensitization related SP, CGRP and glutamic acid release of the ipsilateral L4-6 spinal cord dorsal horn are systematically observed in the induction and maintenance of neuropathic pain, so as to clarify the pathways of TRPV1 in the central sensitization in the induction and maintenance of neuropathic pain. Electroacupuncture is administered to the ipsilateral acupoints "Zu San Li" and " Kun Lun", and the effects of electroacupuncture on the pathways of TRPV1 in the central sensitization in different periods of the SNI model are evaluated, followed by the studies on the counteracting effects of activators of different TRPV1 pathways on electroacupuncture, to elucidate the new mechanism for the therapeutic effects of electroacupuncture on neuropathic pain by regulating TRPV1 pathways in the central sensitization in the spinal cord dorsal horn, and promote the wider and more effective application of acupuncture and moxibustion in the treatment of neuropathic pain.

中枢敏化是神经病理痛关键机制之一。辣椒素受体(TRPV1)在神经病理痛的中枢敏化过程中起着重要作用，但在疼痛发生、维持不同阶段参与中枢敏化的途径未明确。本项目拟建立SNI神经病理痛大鼠模型，系统观察神经病理痛发生、维持不同阶段模型大鼠L4-6脊髓背角cAMP/PKA、PKC功能敏化通路及其敏化相关神经递质SP、CGRP、Glu释放情况，明确神经病理痛发生、维持阶段中枢敏化的TRPV1途径；进而采用电针刺激造模侧"足三里"和"昆仑"穴，观察对不同阶段中枢敏化脊髓背角TRPV1途径的干预效应，并经相关通路激动剂拮抗效应验证，明确电针治疗神经病理痛中枢敏化TRPV1磷酸化调控机制，说明针灸治疗神经病理痛的新原理，推动其更广泛地、更有效地运用于神经病理痛的治疗。

神经病理痛是临床上常见、多发、难治的慢性疼痛疾病，中枢敏化是其发生、维持的关键机制之一。辣椒素受体(TRPV1)在神经病理痛的中枢敏化过程中起着重要作用，但在疼痛发生、维持不同阶段参与中枢敏化的途径未明确。本项目拟建立SNI神经病理痛大鼠模型，系统观察神经病理痛发生、维持不同阶段模型大鼠L4-6脊髓背角PKA、PKC功能敏化通路及其敏化相关神经递质SP、CGRP、Glu释放情况，明确神经病理痛发生、维持阶段中枢敏化的TRPV1途径；进而采用电针刺激造模侧"足三里"和"昆仑"穴，观察对不同阶段中枢敏化脊髓背角TRPV1途径的干预效应，并经相关通路激动剂拮抗效应验证，明确电针治疗神经病理痛中枢敏化TRPV1磷酸化调控机制。研究结果表明，神经病理痛早期中枢敏化可能与术侧脊髓背角TRPV1磷酸化水平表达水平及PKC、PKA及SP、CGRP表达水平升高有关，维持期中枢敏化可能与术侧脊髓背角TRPV1表达水平及PKC、PKA及SP、CGRP表达水平升高有关；不同频率电针对神经病理痛均有良好的镇痛作用，其中2 Hz低频电针对神经病理痛的镇痛效果最佳；电针对神经病理痛发生期的干预可能与其有效抑制PKC、PKA的活化，进而下调术侧脊髓背角TRPV1磷酸化水平、SP、CGRP的表达有关；电针对神经病理痛维持期的干预可能与其有效抑制PKC、PKA的活化，进而下调术侧脊髓背角 TRPV1表达水平和SP、CGRP水平有关。本项目研究结果表明低频电针为治疗神经病理痛的最佳参数，电针治疗神经病理痛可能与其有效抑制PKC、PKA的活化，进而调控脊髓背角TRPV1磷酸化水平或TRPV1表达水平有关，从而下调SP、CGRP的表达水平有关。通过本项目的研究为电针治疗神经病理痛及其频率选择提供科学依据和阐释，以期推动电针更广泛、更好地治疗神经病理痛。