创伤性神经瘤痛觉感受器敏化参与持续性术后痛形成的机制

Persistent pain can be lasting several months or years in 10-50% of individuals after surgeries and remains a major unsolved clinical problem. Traumatic neuroma is presumed to be an important cause of the persistent postoperative pain. In this study, we investigate the role of the peripheral nerve system plays in the formation of traumatic neuroma resultant persistent postoperative pain..We will establish a traumatic neuroma induced persistent postoperative pain mouse model. Guarding pain, thermal and mechanical pain behaviors will be tested. The electrophysiological features of neuroma afferents will be examined using single fiber recording. The expression of pain related ion channels in peripheral nerve system, such as TRPV1 and ASIC (1-3) will be evaluated. Finally, we will study the effects of these ion channels on persistent postoperative pain using TRPV1 or ASIC (1-3) knockout mice..We speculate that the excitability of neuroma afferents is increased whereas the reaction threshold to physical or chemical stimuli is decreased compare with normal afferents. Expression of TRPV1 and ASIC (1-3) can be enhanced in the peripheral nerve system after surgery. TRPV1 is mainly localized on c fibers and is involved in the guarding or thermal pain. ASIC (1-3) are mainly found on Aδ or Aβ fibers. These channels are related to mechanical pain. TRPV1 or ASIC (1-3) konckout mice exhibit diminished pain behavior and afferent excitability compare with the wild type littlemates. Our study will definitely shed light on the potential of TRPV1 or ASIC (1-3) blockers as new pain killers.

约10%-50%的手术患者可发生数月甚至数年的持续性术后痛，其发生机制是亟待研究的重要课题。创伤性神经瘤是持续性术后痛的重要诱因，本研究关注外周神经系统在创伤性神经瘤所致持续性术后痛形成中的作用。.我们将建立小鼠创伤性神经瘤持续术后痛模型,测定其静息、热刺激及机械刺激性痛觉行为改变、神经瘤传入神经纤维电生理特征、外周神经系统TRPV1和ASIC（1-3）痛觉相关离子通道在mRNA及蛋白水平的变化及基因敲除上述离子通道对持续性术后痛的影响。.我们推测创伤性神经瘤传入神经兴奋性增加、对理化刺激的反应阈值降低。TRPV1及ASIC（1-3）表达增加，TRPV1主要分布于C神经纤维与静息性及热刺激性痛有关。ASIC（1-3）主要分布于Aδ、Aβ神经纤维，与机械刺激性痛有关。敲除上述离子通道则持续性术后痛减弱或消失，创伤性神经瘤传入神经兴奋性降低，上述离子通道的特异性阻断剂可能成为新型镇痛药物。

约 10%-50%的手术患者可发生数月甚至数年的持续性术后痛,其发生机制是亟待研究的重要课题。创伤性神经瘤是持续性术后痛的重要诱因,本研究关注外周神经系统在创伤性神经瘤所致持续性术后痛形成中的作用。. 我们成功建立了大鼠创伤性神经瘤持续术后痛模型,测定其静息、热刺激及机械刺激性痛觉行为改变、外周神经系统辣椒素受体（TRPV1）和酸敏感离子通道3（ASIC3）痛觉相关离子通道在 mRNA及蛋白水平的变化。. 我们发现创伤性神经瘤持续术后痛模型大鼠的热刺激性疼痛可持续至术后3周，静息及机械刺激性痛可持续至术后4周。而在传统的急性术后疼痛大鼠模型中，上述三种痛觉改变均只能持续术后1周。据此，我们认为此创伤性神经瘤持续术后痛模型的建模是成功的，具备足够长时间的术后疼痛，可作为持续性术后疼痛模型。应用此模型，我们通过定量RT－PCR法发现TRPV1及ASIC3 mRNA在大鼠足底损伤侧L3－4脊髓结段、相应DRG及坐骨神经内表达增加可持续1周，免疫电泳法发现TRPV1及ASIC3蛋白在上述部位表达增加并持续升高达术后3周。行免疫组织化学染色发现TRPV1及ASIC3蛋白表达于足底损伤侧L3－4脊髓背角、相应DRG及坐骨神经内，并持续到术后3周仍可被检出，与上述免疫电泳法结果一致。双重免疫荧光染色证实TRPV1主要分布于 C 传入神经纤维,而ASIC3主要分布于 Aδ、Aβ传入神经纤维。. 上述研究结果创建了可靠的大鼠持续性术后疼痛模型，为持续性术后疼痛的基础研究提供了有力的研究模型。基于该模型的进一步研究结果提示了TRPV1及ASIC3参与了持续性术后疼痛形成的相关机制，上述离子通道的特异性阻断剂可能成为新型镇痛药物。

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