阿片类引起机械痛觉敏化和镇痛耐受的神经机制研究

慢性痛严重影响患者生存质量，其发病机制复杂，是一个棘手的临床问题。吗啡等阿片类药物是金标准止痛药，是治疗中重度术后疼痛和慢性疼痛的唯一选择。然而，使用阿片类药物会造成多种副作用，如呼吸抑制、便秘、恶心、呕吐等。长期使用阿片类药物伴随着两个主要问题：阿片类药物诱导的痛觉敏化（opioid-induced hypersensitivity, OIH）和镇痛耐受。OIH和镇痛耐受是疼痛控制减弱和药物剂量增加的两个主要驱动因素。因此在临床应用上迫切需要在不影响阿片类药物镇痛作用的同时，减弱或者控制OIH和镇痛耐受的产生，以提高患者的生存质量。为此需要了解产生OIH和镇痛耐受的潜在机制。虽然阿片类药物通过结合μ阿片受体（MORs），抑制疼痛信息传递产生镇痛作用，但介导OIH和镇痛耐受的阿片受体以及细胞类型尚存争议。目前，在疼痛研究领域中的主流观点是，表达在瞬时受体电位香草酸亚型1（TRPV1）伤害性感受器上的MORs，介导了机械型和温度型OIH和镇痛耐受的发生发展。

本论文第一个研究内容（对应第三和四章），研究了外周MORs或表达MOR的神经元在吗啡诱导的机械型和温度型OIH和镇痛耐受中的作用。通过实验发现敲除外周MORs或消融外周MOR表达神经元能阻止吗啡诱导的温度型耐受，但不影响吗啡诱导产生机械型OIH和镇痛耐受。为了进一步验证该结论，采用行为学和电生理方法来对阿片类药物诱导的OIH和镇痛耐受进行研究，包括：（1）使用von Frey纤维丝测试点状机械刺激引起的机械型触诱发痛。（2）使用软测试刷测试动态机械刺激引起的机械型触诱发痛。（3）通过条件位置厌恶实验评估动态机械刺激引起OIH模型小鼠的痛觉厌恶情感成分。（4）通过电生理方法记录脊髓背角浅层神经元是否接受低阈值Aβ纤维的输入和是否诱导出动作电位，以判断脊髓背角机械型触诱发痛通路是否开放。

为了研究外周MORs和MOR表达神经元在吗啡诱导的机械型OIH和镇痛耐受中的作用，使用了多种策略，包括：（1）使用TRPV1^Cre/+;Oprm1^Flox/Flox小鼠条件性地敲除TRPV1⁺神经元上的MORs。（2）使用Tau^DTR/+;TRPV1^Cre/+; Advelin^Flpo/+ 小鼠选择性地消融外周TRPV1⁺神经元。（3）使用Advilin^Cre/+; Oprm1^Flox/Flox小鼠条件性地敲除外周MORs。（4）使用Tau^DTR/+; Oprm1^Cre/+; Advilin^Flpo/+小鼠选择性地消融外周MOR表达神经元。通过行为学和电生理的实验方法在OIH模型中研究表明，外周MORs或MOR表达神经元，介导温度型耐受而不介导机械型OIH和镇痛耐受。

本论文第二个研究内容（对应第五章），研究了投射到外侧臂旁核（lateral parabrachial nucleus, LPBN）的脊髓背角CR神经元在机械型OIH中的作用。研究发现从脊髓背角投射到LPBN的CR神经元调控机械型OIH。反复使用吗啡可增加脊髓背角CR神经元的兴奋性。消融脊髓背角CR神经元或消融从脊髓背角投射到LPBN的CR神经元，可完全阻止机械型OIH的发展。在OIH已经建立的情况下，通过化学遗传抑制LPBN中来自脊髓背角CR神经元的轴突末梢，可以抑制已发展出的机械型OIH。相反，激活LPBN中来自CR神经元的轴突末梢就能诱导野生型小鼠产生机械型触诱发痛。因此，靶向脊髓背角投射到LPBN的CR神经元为解决阿片类药物诱导的机械型OIH和镇痛耐受提供了新的治疗策略。

综上所述，研究表明，投射到LPBN的脊髓CR神经元，而不是外周MORs或表达MOR的神经元，介导了阿片类药物诱导的机械型OIH。因此，为了进一步研究阿片类药物诱导的机械型OIH和镇痛耐受的潜在机制，应该更多地关注中枢神经机制，而不是外周神经机制。

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