Connexin 36 Mediates Orofacial Pain Hypersensitivity Through GluK2 and TRPA1

Qian Li 1• Tian-Le Ma 1• You-Qi Qiu 1• Wen-Qiang Cui 1,2• Teng Chen 1•Wen-Wen Zhang 1
• Jing Wang 3• Qi-Liang Mao-Ying 1• Wen-Li Mi 1•Yan-Qing Wang 1• Yu-Xia Chu 1


1 Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative
Innovation Center, State Key Laboratory of Medical Neurobiology, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China
2 Department of Pain Management, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan 250000, China
3 Department of Nephropathy, The Third Affiliated Hospital of Shenzhen University, Luohu Hospital Group, Shenzhen 518001, China

Abstract

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.

Keywords

Orofacial pain;  Gap junction;  Glutamate receptor ionotropic kainate 2 ; Transient receptor potential A1

[SpringerLink]

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