镜像痛的脊髓机制研究

机械型触诱发痛包含轻度毛刷诱导的动态和轻度压力诱导的点状两种形式，是外周炎症或神经损伤后引起的一种常见且使全世界数百万人变得虚弱的痛反应。在大多数情况下，痛觉敏化会局限在损伤侧，但在某些炎症或神经损伤的条件下，痛觉敏化会蔓延到对侧（通常称为镜像痛），甚至造成全身广泛的痛觉敏化。例如，单侧腕管综合征患者可出现双侧机械型触诱发痛，但仅有少部分复杂区域疼痛综合征患者可以诱导出双侧机械型触诱发痛。单侧注射完全弗氏佐剂或角叉菜胶能够诱导出大鼠的双侧机械型触诱发痛，而大部分情况下神经损伤仅诱导出小鼠的单侧机械型触诱发痛。

局部损伤是如何诱导产生双侧的机械型触诱发痛？迄今为止，人们对这种偏侧性是如何被调节的还知之甚少。机械型触诱发痛的通路是本来就存在，但正常情况下在脊髓背角是被门控的。有关机械型触诱发痛的偏侧性控制的机制可以通过研究双侧机械型触诱发痛的门控机制方面进行研究。根据疼痛的门控理论，脊髓背角痛觉传递神经元（T神经元）接受来自低阈值Aβ机械型感受器的输入。然而，低阈值Aβ机械型感受器的输入通常在脊髓背角被抑制性神经元门控。由外周炎症或神经损伤引起痛觉传递神经元兴奋性输出的增强或抑制性神经元的去抑制可以打开脊髓背角的门控，进而使非痛机械型刺激引起痛觉反应。部分研究探讨了T神经元和抑制性神经元在躯体感觉机械型触诱发痛中的作用，这些研究进一步支持门控理论。

尽管目前关于脊髓背角痛传递神经元（T神经元）和抑制性神经元类型的鉴定取得了进展，但仍有一个尚未解决的主要问题：是什么驱动和影响T神经元和抑制性神经元的兴奋性，进而影响双侧机械型触诱发痛中脊髓背角的门控。研究表明双侧机械型触诱发痛可能是通过调节脊髓背角T神经元和抑制性神经元的兴奋性，进而介导由双侧下行调节的脊髓背角的神经环路。在外周炎症或神经损伤后激活的胶质细胞也可能影响脊髓背角T神经元和抑制性神经元的兴奋性。多个研究团队的研究结果也指出激活的星型胶质细胞在双侧的机械型触诱发痛的发展过程中发挥了关键性的作用。然而，小胶质细胞在调控机械型触诱发痛偏侧性中的作用仍然是存在争议的。例如，研究指出鞘内注射小胶质细胞激活的选择性抑制剂-米诺环素能够抑制角叉菜胶诱导的对侧机械型触诱发痛。与此相反，另一份研究指出激活脊髓的小胶质细胞阻止角叉菜胶诱导大鼠对侧的机械型触诱发痛的发展。

论文的第一部分研究（第三章和第四章）旨在探究小胶质细胞在镜像痛中的作用。为了探究小胶质细胞在镜像痛中的作用：（1）本研究筛选出六种单侧损伤诱导双侧动态或点状的机械型触诱发痛小鼠模型进行功能丧失的研究；（2）为了探究双侧机械型触诱发痛的表型与脊髓背角门控的双侧改变是否高度相关，本研究在六种小鼠模型的“背根神经节-背根-脊髓切片”中记录低阈值Aβ纤维刺激诱发的脊髓背角浅层神经元的输入和输出；（3）本研究使用遗传策略来耗尽这些转基因小鼠的小胶质细胞。出人意料的是，中枢神经系统小胶质细胞的敲除不能阻止双侧动态或点状的机械型触诱发痛。此外，与行为学结果一致的是小胶质细胞敲除不能阻止脊髓背角双侧Aβ门控的开放。这些研究结果表明小胶质细胞在启动双侧机械型触诱发痛的过程中并不是必需的。本研究的第一部分结果挑战了小胶质细胞在控制小鼠双侧机械型触诱发痛偏侧性过程中的作用。进一步研究需要深入探究小胶质细胞在调控双侧机械型触诱发痛偏侧性过程中是否是病因学或物种特异的。

论文的第二部分研究（第五章）旨在探究调控双侧机械型触诱发痛偏侧性过程中的神经机制。第五章研究脊髓κ阿片受体（KOR）在调控小鼠双侧机械型触诱发痛偏侧性过程中的作用。为了探究脊髓背角κ阿片受体在调控小鼠机械型触诱发痛中的作用：（1）本研究进行全细胞膜片钳记录脊髓背角κ阿片受体神经元，结果表明在辣椒素处理后对侧脊髓背角KOR神经元的兴奋性增加；（2）鞘内注射KOR拮抗剂可以阻止辣椒素模型小鼠中脊髓背角Aβ门控的开放，此部分结果表明脊髓背角κ阿片受体在辣椒素模型小鼠诱导对侧Aβ门控的开放是必需的；（3）与鞘内注射κ阿片受体拮抗剂实验结果一致的是，采用Lbx1Cre/Oprk1fl/fl 小鼠敲除脊髓背角κ阿片受体同样可以阻止辣椒素模型小鼠中脊髓背角Aβ门控的开放。这些研究结果表明通过调节脊髓背角κ阿片受体神经元的兴奋性进而调控机械型触诱发痛的偏侧性。

综上所述，这些研究结果共同表明小胶质细胞无论在伤害刺激诱导的触诱发痛的过程中是否发挥作用，小胶质细胞对于镜像痛的诱导并不是必需的。与此同时，脊髓背角神经元中的KORs控制镜像痛的发生发展可能是通过提高此类神经元的兴奋性进而打开对侧介导镜像痛的脊髓背角的门控。因此，脊髓背角神经元中的KORs而非小胶质细胞在镜像痛的发展过程中是扮演重要的角色。在后续的研究中，需要进一步解析脊髓背角KORs介导镜像痛发生发展的分子细胞和神经机制。

Mechanical allodynia (MA), which includes gentle brushing-evoked dynamic and light pressure-evoked punctate forms, is a common and debilitating symptom experienced by millions of patients worldwide following peripheral inflammation or nerve injury. In both humans and animals, some local unilateral injuries lead to full-blown bilateral MA; however, most unilateral injuries in human patients and commonly used inflammatory and neuropathic pain models in animals usually manifest mechanical allodynia on the side ipsilateral to the injury (called mirror-image pain), but not the contralateral uninjured side. For example, patients with unilateral carpal tunnel syndrome can experience bilateral MA, but only a minority of patients with complex regional pain syndrome do so. Unilateral injection of complete Freund's adjuvant (CFA) or carrageenan can induce bilateral MA in rats, while nerve injury in most cases only evokes unilateral MA in mice.

How can certain unilateral injuries produce bilateral MA? To date, how such laterality is controlled remains poorly understood. MA pathways pre-exist, but normally “gated” in the spinal dorsal horn. The question of the control of MA laterality can be addressed by examining the gate control mechanisms of the bilaterality of MA. According to the gate control theory of pain, pain transmission neurons (T neurons) in the spinal dorsal horn (SDH) receive inputs from low-threshold Aβ mechanoreceptors; however, these inputs are normally gated by inhibitory neurons (INs) in the SDH. Enhanced excitatory outputs from T neurons or disinhibition of INs caused by peripheral inflammation or nerve injury can open the gate, allowing non-painful mechanical stimuli to generate the perception of pain. Several studies have addressed the identities of T neurons and INs involved in somatosensory MA that support the gate control theory of pain.

Despite recent progress regarding the identities of T neurons and INs, one major unanswered question remains: what are the main forces that drive and influence the excitability of T neurons and INs, to subsequently affect the gate control of bilateral MA pathways in the SDH? Some studies suggest that bilateral MA is mediated by bilateral descending modulation of dorsal horn circuits, presumably by modulating the excitability of T neurons and INs in the SDH. Activated glial cells may also influence the excitability of T neurons and INs in the SDH following peripheral inflammation or nerve injury. Several groups have supported the critical role of activated astrocytes in the development of bilateral MA. However, the role of microglia in the control of MA laterality remains controversial. For instance, Schreiber et al., reported that intrathecal administration of minocycline, a selective inhibitor of microglial activation, inhibits the development of carrageenan-induced contralateral MA in mice. In contrast, Choi et al., reported that activated spinal microglia prevent the development of carrageenan-induced contralateral MA in rats.

   The first part of this thesis (Chapters 3 and 4) aimed to investigate the role of microglia in the control of MA in mice. To this end, (1) we screened behavioral phenotypes in 6 pain models of unilateral injury-induced bilateral dynamic and punctate MA to perform loss-of-function studies; (2) to determine whether the behavioral signs of bilateral MA are correlated with a bilateral change in the gate control within the SDH, in dorsal root ganglion (DRG)–dorsal root–sagittal spinal cord slice preparations, we recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs of SDH neurons in the 6 MA models; and (3) we used genetic strategies to deplete microglia in these transgenic mice. Surprisingly, central microglial depletion did not prevent the induction of bilateral dynamic or punctate MA. Moreover, consistent with the behavioral tests, microglial depletion did not prevent the opening of bilateral gates for Aβ pathways in the superficial dorsal horn. These results suggest that microglia are not required for the initiation of bilateral MA in mice. The first part of this study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether role of microglia in the control of MA laterality is etiology- or species-specific.

The second part of this thesis (Chapter 5) went on to explore neural mechanisms underlying laterality control of mechanical allodynia. Chapter 5 examined the role of spinal kappa opioid receptors (KORs) in the laterality control of MA in mice. To this end, (1) we performed whole-cell patch clamp recording of KOR⁺ neurons in the spinal dorsal horn and found increased excitability of contralateral KOR⁺ neurons upon hindpaw capsaicin injection; (2) i.t application of KOR antagonist nor-BNI before hindpaw capsaicin injection prevented the opening of contralateral Aβ pathways, suggesting that spinal KORs are required for the induction of contralateral Aβ pathways in hindpaw capsaicin model; and (3) consistent with i.t. injection of KOR antagonist, genetic knockout of KORs from dorsal horn neurons with Lbx1^Cre/Oprk1^fl/fl mice also prevented the opening of contralateral Aβ pathways in hindpaw capsaicin model. These results demonstrate that spinal KORs could control the laterality of mechanical allodynia via modulating the excitability of KOR⁺ neurons in the spinal dorsal horn.

Overall, these data collectively show that microglia, no matter what kind of role they may play in nociception-induced mechanical allodynia, they are not required for the initiation of contralateral allodynia; in the meantime, KORs from dorsal horn neurons control the laterality of mechanical allodynia, possibility via increasing the excitability of these neurons and subsequently opened the gate for contralateral mechanical allodynia pathways. Therefore, KORs from dorsal horn neurons, but not microglia, are required for the development of mirror-image pain. In the future, more experiments are warranted to further dissect the underlying mechanisms for the laterality control of mirror-image pain by dorsal horn KORs.

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