A role for LGI1 in regulating pain sensitivity
A role for LGI1 in regulating pain sensitivity
复制标题
DOI：
10.1101/2023.09.13.557645
复制
发表时间：
2023-09
期刊：
影响因子：
--
通讯作者：
Adham Farah;Ivan Paul;Hoi Cheng;Yuhe Su;Piotr Poplawski;Mandy Tseng;John M. Dawes
中科院分区：
文献类型：
--
作者：
Adham Farah;Ivan Paul;Hoi Cheng;Yuhe Su;Piotr Poplawski;Mandy Tseng;John M. Dawes
慢性疼痛是一个主要的未满足的临床需求。神经性疼痛是由于躯体感觉神经系统的损伤或疾病引起的疼痛，在慢性疼痛病例中占相当大的比例，影响约8%的一般人群。神经元过度兴奋是神经病理性疼痛的关键驱动因素。亮氨酸胶质瘤失活蛋白1（LGI1）是一种分泌蛋白，已知其调节神经系统内的兴奋性，并且是来自神经性疼痛患者的自身抗体的靶标。阻断或降低抗体水平的疗法在缓解这些患者的疼痛方面非常有效，这表明LGI1在临床疼痛中起着重要作用。在这里，我们研究了LGI1在调节疼痛中的作用，使用小鼠模型来特异性地消融神经元群体中的LGI1。LGI1已经在大脑水平上得到了很好的研究。在这里，我们表明，LGI1是高度表达的背根神经节（DRG）神经元和脊髓背角神经元。使用转基因小鼠，我们消融了伤害感受器（LGI1fl/Nav1.8（+/-））或所有DRG和脊髓神经元（LGI1fl/Hoxb8（+/-））中的LGI1。在急性疼痛试验中，与同窝对照相比，观察到轻度表型，DRG神经元兴奋性变化有限。在福尔马林试验的第一阶段中未观察到差异，然而，与同窝对照相比，LGI1fl/Hoxb8（+/-）小鼠在第二阶段中表现出疼痛反应行为的显著增加。使用备用神经损伤模型，我们评估了LGI1消融对神经性疼痛样行为的影响。与对照组相比，LGI1fl/Nav1.8（+/-）小鼠在神经损伤诱导的机械超敏反应、刷毛诱发的异常性疼痛或自发性疼痛行为方面无差异。然而，LGI1fl/Hoxb8（+/-）小鼠显示机械超敏反应和异常性疼痛显著加重。这些数据表明LGI 1在调节疼痛敏感性方面发挥作用，特别是在神经损伤的情况下。我们认为这种效应可能是在脊髓水平介导的，因为在伤害感受器中特异性消融LGI1后没有观察到差异。脊髓背角神经元在门控神经损伤引起的机械性疼痛中起重要作用，我们的研究结果表明LGI1在这一过程中起重要作用。
Chronic pain represents a major unmet clinical need. Neuropathic pain, that is pain arising due to damage or disease of the somatosensory nervous system, represents a sizeable proportion of chronic pain cases, affecting around 8% of the general population. Neuronal hyperexcitability is a key driver of neuropathic pain. Leucine glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are highly effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have studied the role of LGI1 in regulating pain using mouse models to specifically ablate LGI1 in neuron populations. LGI1 has been well studied at the level of the brain. Here we show that LGI1 is highly expressed in dorsal root ganglion (DRG) neurons and in dorsal horn neurons of the spinal cord. Using transgenic mice, we ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8(+/-)), or in all DRG and spinal neurons (LGI1fl/Hoxb8(+/-)). On acute pain assays, mild phenotypes were observed when compared to littermate controls with limited changes in DRG neuron excitability. No differences were seen in the first phase of the formalin test, however LGI1fl/Hoxb8(+/-) mice displayed a significant increase in nocifensive behaviours in the second phase compared to littermate controls. Using the spared nerve injury model, we assessed the impact of LGI1 ablation on neuropathic pain-like behaviours. LGI1fl/Nav1.8(+/-) mice showed no differences in nerve injury induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared to controls. However, LGI1fl/Hoxb8(+/-) mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. These data show that LGI1 has a role in regulating pain sensitivity particularly in the context of nerve injury. We suggest this effect is likely mediated at the spinal level since no differences were observed following specific ablation of LGI1 in nociceptors. Neurons in dorsal horn of the spinal cord are important in gating nerve injury induced mechanical pain and our findings suggest that LGI1 plays an important role in this process.