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Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling
- Source :
- The journal of pain. 21(1-2)
- Publication Year :
- 2019
-
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.
- Subjects :
- Male
Orofacial pain
Connexin
03 medical and health sciences
Trigeminal ganglion
Mice
0302 clinical medicine
030202 anesthesiology
Facial Pain
medicine
Animals
Humans
TRPA1 Cation Channel
Protein kinase C
Protein Kinase C
Trigeminal nerve
business.industry
Calcium channel
Gap junction
Gap Junctions
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
Anesthesiology and Pain Medicine
Neurology
Trigeminal Ganglion
Hyperalgesia
Neurology (clinical)
Calcium Channels
medicine.symptom
business
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- ISSN :
- 15288447
- Volume :
- 21
- Issue :
- 1-2
- Database :
- OpenAIRE
- Journal :
- The journal of pain
- Accession number :
- edsair.doi.dedup.....733185ba49e3b56197492590f18e87a6