Highlights
- •Infraorbital nerve injury induces primary and secondary orofacial hyperalgesia.
- •Cavα2δ1 contributes to the development of secondary orofacial hyperalgesia.
- •Cavα2δ1 mediates secondary orofacial hyperalgesia through PKC-TRPA1/GJ pathway.
Abstract
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 α2δ1 (Cavα2δ1) 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
Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering
RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of
PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition
reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION.
Cavα2δ1 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 Cavα2δ1 contributes to the development of secondary hyperalgesia through its
downstream PKC-TRPA1/GJ signaling pathways.
Perspective
This study demonstrates that the activation of Cavα2δ1 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 Cavα2δ1, TRPA1,
or GJs might be effective treatments for nerve injury-induced spreading of orofacial
pain.
Graphical Abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 05, 2019
Accepted:
August 6,
2019
Received in revised form:
July 6,
2019
Received:
March 12,
2019
Footnotes
Authors’ contributions: YX.C. and WQ.C. designed the experiments and wrote the paper; WQ.C., YX.C., F.X., and T.C. carried out most of the experiments and image analysis; L.G., Y.F., XM.H., W.Y., LX.D., and WW.Z. performed the experiments; QL.MY., WL.M., and YQ.W. provided valuable advice on the research. All authors discussed the results and the manuscript.
Disclosures: This study was financially supported by National Natural Science Foundation of China (81971056, 31600852, 81771202, 81873101), National Key R&D Program of China (2017YFB0403803), and Development Project of Shanghai Peak Disciplines-Integrated Medicine (20180101).
The authors declare that there is no conflict of interest regarding the publication of this paper.
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Copyright
© 2019 by United States Association for the Study of Pain, Inc.
