Peripheral neurostimulation within the trigeminal nerve territory has been used for pain alleviation during migraine attacks, but the mechanistic basis of this non-invasive intervention is still poorly understood. In this study, we investigated the therapeutic role of peripheral stimulation of the trigeminal nerve, which provides homosegmental innervation to intracranial structures, by assessing analgesic effects in a nitroglycerin-induced rat model of migraine. As a result of neurogenic inflammatory responses in the trigeminal nervous system, plasma protein extravasation was induced in facial skin by applying noxious stimulation to the dura mater. Noxious chemical stimulation of the dura mater led to protein extravasation in facial cutaneous tissues and caused mechanical sensitivity. Trigeminal ganglion neurons were double-labeled via retrograde tracing to detect bifurcated axons. Extracellular recordings of wide dynamic range neurons in the spinal trigeminal nucleus caudalis demonstrated the convergence and interaction of inputs from facial tissues and the dura mater. Peripheral neurostimulation of homotopic facial tissues represented segmental pain inhibition on cephalic cutaneous allodynia in the migraine model. The results indicated that facial territories and intracranial structures were directly connected with each other through bifurcated double-labeled neurons in the trigeminal ganglion and through second-order wide dynamic range neurons. Homotopic stimulation at the C-fiber intensity threshold resulted in much stronger inhibition of analgesia than the same intensity of heterotopic stimulation. These results provide novel evidence for the neurological bases through which peripheral neurostimulation may be effective in treating migraine in clinical practice.

三叉神经区域内的周围神经刺激已被用于缓解偏头痛发作期间的疼痛，但是这种非侵入性干预的机制基础仍知之甚少。在这项研究中，我们通过评估硝酸甘油诱导的偏头痛大鼠模型的镇痛作用，研究了三叉神经外围刺激的治疗作用，该刺激为颅内结构提供了同节神经支配。三叉神经系统中神经性炎症反应的结果是，通过对硬脑膜施加有害刺激，在面部皮肤中引起血浆蛋白外渗。硬脑膜的有害化学刺激导致面部皮肤组织中的蛋白质外渗并引起机械敏感性。通过逆行追踪对三叉神经节神经元进行双重标记，以检测分叉的轴突。脊柱三叉神经尾核中宽动态范围神经元的细胞外记录显示了面部组织和硬脑膜输入的融合和相互作用。在偏头痛模型中，同态面部组织的周围神经刺激代表了对头皮异常性疼痛的节段性疼痛抑制。结果表明，面部区域和颅内结构通过三叉神经节中的分叉的双标记神经元和通过二阶宽动态范围神经元直接相互连接。在C纤维强度阈值下的同位刺激比相同强度的异位刺激对镇痛的抑制作用强得多。