Trigeminal neuralgia is a debilitating condition, and the pain easily spreads to other parts of the face. Here, we established a mouse model of partial transection of the infraorbital nerve (pT-ION) and found that the Connexin 36 (Cx36) inhibitor mefloquine caused greater alleviation of pT-ION-induced cold allodynia compared to the reduction of mechanical allodynia. Mefloquine reversed the pT-ION-induced upregulation of Cx36, glutamate receptor ionotropic kainate 2 (GluK2), transient receptor potential ankyrin 1 (TRPA1), and phosphorylated extracellular signal regulated kinase (p-ERK) in the trigeminal ganglion. Cold allodynia but not mechanical allodynia induced by pT-ION or by virus-mediated overexpression of Cx36 in the trigeminal ganglion was reversed by the GluK2 antagonist NS102, and knocking down Cx36 expression in Nav1.8-expressing nociceptors by injecting virus into the orofacial skin area of Nav1.8-Cre mice attenuated cold allodynia but not mechanical allodynia. In conclusion, we show that Cx36 contributes greatly to the development of orofacial pain hypersensitivity through GluK2, TRPA1, and p-ERK signaling.

三叉神经痛是一种使人衰弱的疾病，疼痛很容易扩散到面部的其他部位。在这里，我们建立了眶下神经部分横断（pT-ION）的小鼠模型，发现与机械性异常性疼痛的减少相比，连接蛋白 36（Cx36）抑制剂甲氟喹可以更大程度地缓解 pT-ION 诱导的冷异常性疼痛。甲氟喹逆转了 pT-ION 诱导的三叉神经节中 Cx36、谷氨酸受体离子型红藻氨酸 2 (GluK2)、瞬时受体电位锚蛋白 1 (TRPA1) 和磷酸化细胞外信号调节激酶 (p-ERK) 的上调。 GluK2 拮抗剂 NS102 可以逆转由 pT-ION 或病毒介导的三叉神经节中 Cx36 过度表达引起的冷异常性疼痛，但不是机械性异常性疼痛，并且通过将病毒注射到口面部皮肤来敲低表达 Nav1.8 的伤害感受器中的 Cx36 表达Nav1.8-Cre 小鼠的区域减轻了冷异常性疼痛，但没有减轻机械性异常性疼痛。总之，我们表明 Cx36 通过 GluK2、TRPA1 和 p-ERK 信号传导极大地促进口面部疼痛过敏的发生。