Inflammopharmacology. 2021 Sep 12.doi: 10.1007/s10787-021-00873-0. Online ahead of print.

The role of dorsal root ganglia alpha-7 nicotinic acetylcholine receptor in complete Freund’s adjuvant-induced chronic inflammatory pain

Xiaoyu Zhang  1   2   3 Fangxia Xu  1 Lijuan Wang  1 Jinbao Li  1 Jianhai Zhang  4 Lina Huang  5 Affiliations

Abstract

Background: Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) was reported to have a critical role in the regulation of pain sensitivity and neuroinflammation. However, the expression level of α7 nAChR in dorsal root ganglion (DRG) and the underlying neuroinflammatory mechanisms associated with hyperalgesia are still unknown.

Methods: In the present study, the expression and mechanism of α7 nAChR in chronic inflammatory pain was investigated using a complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain model. Subsequently, a series of assays including immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed.

Results: α7 nAChR was mostly colocalized with NeuN in DRG and upregulated after CFA injection. Microinjection of α7 nAChR siRNA into ipsilateral L4/5 DRGs aggravated the CFA-induced pain hypersensitivity. Intrathecal α7 nAChR agonist GTS-21 attenuated the development of CFA-induced mechanical and temperature-related pain hypersensitivities. In neuronal the SH-SY5Y cell line, the knockdown of α7 nAChRs triggered the upregulation of TRAF6 and NF-κB under CFA-induced inflammatory conditions, while agitation of α7 nAChR suppressed the TRAF6/NF-κB activation. α7 nAChR siRNA also exacerbated the secretion of pro-inflammatory mediators from LPS-induced SH-SY5Y cells. Conversely, α7 nAChR-specific agonist GTS-21 diminished the release of interleukin-1beta (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNFα) in SH-SY5Y cells under inflammatory conditions. Mechanistically, the modulation of pain sensitivity and neuroinflammatory action of α7 nAChR may be mediated by the TRAF6/NF-κB signaling pathway.

Conclusions: The findings of this study suggest that α7 nAChR may be potentially utilized as a therapeutic target for therapeutics of chronic inflammatory pain.

Keywords: Dorsal root ganglion (DRG); Inflammatory pain; NF-κB; TRAF6; α7 nAChR.

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