Department of Neurophysiology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
J Neurophysiol. 2021 May 1;125(5):1598-1611. doi: 10.1152/jn.00348.2020. Epub 2021 Feb 17.
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 hindlimb (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, and 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 nonspecific, myofascial low back pain through repetitive nociceptive stimuli. Blocking fractalkine signaling by neutralizing antibodies completely prevented spinal sensitization induced by repetitive mild nociceptive input [2 nerve growth factor (NGF) injections into the multifidus muscle] Conversely, fractalkine given intrathecally caused the same pattern of spinal sensitization as the nociceptive NGF injections. Fractalkine signaling is critically involved in sensitization of dorsal horn neurons induced by repeated nociceptive low back muscle stimulation and may hence be a potential target for the prevention of nonspecific, myofascial low back pain.
激活的小胶质细胞释放的神经活性物质导致许多慢性疼痛动物模型中脊髓背角神经元的过度兴奋。一个重要的反馈回路机制是通过初级传入末梢和背角神经元释放 fractalkine (CX3CL1)，并与小胶质细胞上的 CX3CR1 受体结合。我们研究了 fractalkine 信号在由腰椎多裂肌中两次注射神经生长因子 (NGF) 引起的潜伏和显性脊髓敏化中的作用，作为肌筋膜下腰痛的模型。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。在鞘内给予载体的情况下，两次 NGF 注射导致对深部组织刺激有反应的神经元比例增加（41%），感受野扩展到后肢（15%），静息活动增加（53%）。通过连续鞘内给予中和抗体阻断 fractalkine 信号完全阻止了这些脊髓敏化的迹象，其程度与以前使用小胶质细胞抑制剂米诺环素的研究相似。相反， fractalkine 本身以剂量依赖性的方式诱导类似的敏化（200ng/ml 时：45%的深部组织反应、24%的感受野扩展和 45%的静息活动），类似于肌肉内 NGF 注射引起的重复伤害性刺激。随后单次 NGF 注射没有相加作用。我们的数据表明，通过 CX3CL1-CX3CR1 途径的神经元-小胶质细胞信号在通过重复伤害性刺激启动非特异性、肌筋膜下腰痛中起着关键作用。通过中和抗体阻断 fractalkine 信号完全阻止了由重复轻度伤害性传入引起的脊髓敏化[2 次向多裂肌注射神经生长因子 (NGF)]。相反，鞘内给予 fractalkine 引起与伤害性 NGF 注射相同的脊髓敏化模式。Fractalkine 信号在由重复伤害性腰骶肌刺激引起的背角神经元敏化中起着关键作用，因此可能是预防非特异性、肌筋膜下腰痛的潜在靶点。
