Neuroactive substances released by activated microglia contribute to hyperexcitability of spinal dorsal horn neurons in many animal models of chronic pain. An important feedback loop mechanism is via release of fractalkine (CX3CL1) from primary afferent terminals and dorsal horn neurons and binding to CX3CR1 receptors on microglial cells. We studied the involvement of fractalkine signaling in latent and manifest spinal sensitization induced by two injections of nerve growth factor (NGF) into the lumbar multifidus muscle as a model for myofascial low back pain. Single dorsal horn neurons were recorded in vivo to study their receptive fields and spontaneous activity. Under intrathecal vehicle application, the two NGF injections led to an increased proportion of neurons responding to stimulation of deep tissues (41%), to receptive field expansion into the hind limb (15%), and to resting activity (53%). Blocking fractalkine signaling by continuous intrathecal administration of neutralizing antibodies completely prevented these signs of spinal sensitization to a similar extent as in a previous study with the microglia inhibitor minocycline. Reversely, fractalkine itself induced similar sensitization in a dose dependent manner (for 200 ng/ml: 45% deep tissue responses, 24% receptive field expansion, 45% resting activity) as repeated nociceptive stimulation by intramuscular NGF injections. A subsequent single NGF injection did not have an additive effect. Our data suggest that neuron to microglia signaling via the CX3CL1-CX3CR1 pathway is critically involved in the initiation of non-specific, myofascial low back pain through repetitive nociceptive stimuli.

中文翻译：

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脊髓分形蛋白 (CX3CL1) 信号传导对于实验性非特异性肌筋膜腰痛中的神经元致敏至关重要

在许多慢性疼痛动物模型中，由活化的小胶质细胞释放的神经活性物质导致脊髓背角神经元过度兴奋。一个重要的反馈回路机制是通过初级传入末端和背角神经元释放fractalkine (CX3CL1) 并与小胶质细胞上的 CX3CR1 受体结合。我们研究了在腰椎多裂肌中两次注射神经生长因子 (NGF) 作为肌筋膜腰痛模型诱导的潜在和明显的脊髓致敏中 fractalkine 信号传导的参与。在体内记录单个背角神经元以研究它们的感受野和自发活动。在鞘内载体应用下，两次 NGF 注射导致响应深层组织刺激的神经元比例增加（41%），感受野扩展至后肢（15%）和静息活动（53%）。通过连续鞘内施用中和抗体来阻断 fractalkine 信号传导完全阻止了这些脊髓致敏迹象，其程度与先前使用小胶质细胞抑制剂米诺环素的研究相似。相反，fractalkine 本身以剂量依赖性方式诱导类似的致敏作用（对于 200 ng/ml：45% 的深层组织反应，24% 的感受野扩大，45% 的静息活动）作为肌肉内 NGF 注射的重复伤害性刺激。随后的单次 NGF 注射没有附加效应。我们的数据表明，通过 CX3CL1-CX3CR1 通路的神经元到小胶质细胞的信号传导与通过重复伤害性刺激引起的非特异性肌筋膜腰痛密切相关。