下丘脑Dyn-脊髓KOR系统控制触诱发痛和吗啡诱导的机械痛觉敏化和镇痛耐受

  机械触诱发痛指的是由非痛的轻触刺激所诱发的异常疼痛现象，它是炎症性和神经病理性慢性疼痛的一个特征性症状。触诱发痛对吗啡等阿片类镇痛药相对不敏感，属于顽固性和难治性的异常疼痛。在少数患者中，局部炎症或神经损伤可能会引起长时程、全身性的机械痛觉敏化（触诱发痛），而对于大多数患者来说，疼痛可能是短暂的或局限于损伤侧。然而，其潜在神经控制机制，特别是侧性控制，目前仍知之甚少。

  论文的第一部分研究（第3章）旨在探究触诱发痛的时程和侧性控制机制。该研究工作主要在各种基因工程的小鼠上，应用行为学测试和脊髓及脑片电生理记录，结合病毒、光化学遗传学、脑立体定位、免疫组化和原位杂交等技术解析控制机械触诱发痛时空特征的的脑-脊髓下行调控机制。我们的研究发现，神经损伤或致炎剂导致投射到脊髓的下丘脑Pdyn阳性的神经元的兴奋性升高，通过下丘脑强啡肽（Dyn）-脊髓κ阿片受体（KOR）轴抑制足底注射辣椒素引起的触诱发痛的时程和外周神经损伤（SNI 模型）引起的触诱发痛单侧变成双侧。当我们消融或抑制投射到脊髓的下丘脑Pdyn阳性的神经元，敲除投射到脊髓的下丘脑神经元的Pdyn基因或脊髓鞘内阻断KOR受体，能够导致持久的双侧机械触诱发痛。相反，激活投射到脊髓的下丘脑Pdyn神经元或脊髓鞘内激活KOR受体能够抑制持续的双侧触诱发痛。以上研究表明，下丘脑强啡肽（Dyn）-脊髓κ 阿片受体（KOR），从时间和空间上控制外周炎症和或神经损伤引起的机械痛觉敏化（触诱发痛）的持续时间和扩散范围。

  当前，对于中重度慢性疼痛，吗啡等阿片类药物仍然是主要的镇痛手段。然而，长期反复使用阿片类镇痛药会引起镇痛耐受和痛觉敏化（OIH）等严重副作用。

  本论文的第二部分研究（第4章）聚焦探究阿片类引起的机械型痛觉敏化和镇痛耐受的中枢神经机制。本部分研究发现，“下丘脑强啡肽 （Dyn）-脊髓κ阿片受体（KOR）”抑制系统控制吗啡诱导的机械型痛觉敏化（OIH）和相应的镇痛耐受。我们观察到，从下丘脑背内侧区投射到脊髓背角的Pdyn神经元（HSP^Pdyn）接收来自富含μ阿片受体（MOR）的多个疼痛相关脑区的直接投射，吗啡反复给药使 HSP^Pdyn 神经元发生了长时程抑制。采用化学遗传学激活HSP^Pdyn神经元轴突末梢，或鞘内注射KOR 激动剂Dyn A，可以挽救已经诱导完成的吗啡机械型OIH和镇痛耐受。相反，遗传学消融/沉默HSP^Pdyn神经元，选择性敲除表达在HSP^Pdyn神经元中的Pdyn基因，或鞘内注射KOR拮抗剂nor-BNI，可以延长吗啡反复给药导致的机械痛觉敏化的持续时间并引起吗啡镇痛抵抗。最后，我们的研究发现，采用化学遗传学激活HSP^Pdyn神经元轴突末梢，可以阻断阿片类反复给药引起的机械型OIH和镇痛耐受的发生。因此，靶向上述“下丘脑Dyn-脊髓KOR”轴可以逆转吗啡反复给药引起的机械型痛觉敏化和相应的镇痛耐受。

  下丘脑到脊髓的DYN-KOR下行系统功能减弱能延长神经损伤和炎症导致的机械触诱发痛的时程和范围，并且导致吗啡诱导的痛觉敏化和镇痛耐受的产生。激活DYN-KOR系统能够抑制机械触诱发痛的时程和范围，同时阻止吗啡诱导的痛觉敏化和镇痛耐受产生。本研究结果可以为临床前研究和/或临床试验提供一种基于机制的、模式特异性的策略，以解决临床上慢性疼痛的治疗。

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