Calcium Channel 21 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling

Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extraterritorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit alpha 2 delta 1 (Cav alpha 2 delta 1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cav alpha 2 delta 1 antagonist gabapentin and by the expression of Cav alpha 2 delta 1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cav alpha 2 delta 1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cav alpha 2 delta 1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cav alpha 2 delta 1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways. Perspective: This study demonstrates that the activation of Cav alpha 2 delta 1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cav alpha 2 delta 1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain. (C) 2020 U.S. Association for the Study of Pain. Published by Elsevier Inc. All rights reserved.