The nAChR Chaperone TMEM35a (NACHO) Contributes to the Development of Hyperalgesia in Mice

Sergey G. Khasabov, Victoria M. Rogness, Montana B. Beeson, Lucy Vulchanova-Hart, Li Lian Yuan, Donald A. Simone, Phu V. Tran

Research output: Contribution to journalArticlepeer-review

Abstract

Pain is a major health problem, affecting over fifty million adults in the US alone, with significant economic cost in medical care and lost productivity. Despite evidence implicating nicotinic acetylcholine receptors (nAChRs) in pathological pain, their specific contribution to pain processing in the spinal cord remains unclear given their presence in both neuronal and non-neuronal cell types. Here we investigated if loss of neuronal-specific TMEM35a (NACHO), a novel chaperone for functional expression of the homomeric α7 and assembly of the heteromeric α3, α4, and α6-containing nAChRs, modulates pain in mice. Mice with tmem35a deletion exhibited thermal hyperalgesia and mechanical allodynia. Intrathecal administration of nicotine and the α7-specific agonist, PHA543613, produced analgesic responses to noxious heat and mechanical stimuli in tmem35a KO mice, respectively, suggesting residual expression of these receptors or off-target effects. Since NACHO is expressed only in neurons, these findings indicate that neuronal α7 nAChR in the spinal cord contributes to heat nociception. To further determine the molecular basis underlying the pain phenotype, we analyzed the spinal cord transcriptome. Compared to WT control, the spinal cord of tmem35a KO mice exhibited 72 differentially-expressed genes (DEGs). These DEGs were mapped onto functional gene networks using the knowledge-based database, Ingenuity Pathway Analysis, and suggests increased neuroinflammation as a potential contributing factor for the hyperalgesia in tmem35a KO mice. Collectively, these findings implicate a heightened inflammatory response in the absence of neuronal NACHO activity. Additional studies are needed to determine the precise mechanism by which NACHO in the spinal cord modulates pain.

Original languageEnglish (US)
Pages (from-to)74-87
Number of pages14
JournalNeuroscience
Volume457
DOIs
StatePublished - Mar 1 2021

Bibliographical note

Funding Information:
We thank Dr. Michael Georgieff for his generosity in financial support via the Harrison Chair Endowment to continue this important research. We thank Dr. Ralph Loring (Northeastern University) for his contribution in reviewing and editing our manuscript. This work was supported by the Vikings? Children Fund and Minnesota Medical Foundation to P.V.T. and NIH grants CA241627 and HL135895 to D.A.S. Conceptualization, S.G.K. D.A.S. and P.V.T; Data curation, S.G.K. V.M.R, M.M.B and P.V.T; Formal analysis, S.G.K and P.V.T; Funding acquisition, D.A.S and P.V.T; Investigation, S.G.K and P.V.T; Methodology, S.G.K and P.V.T; Project administration, P.V.T; Resources, M.M.B, L.V-H, L-L.Y, D.A.S and P.V.T; Supervision, P.V.T; Writing ? original draft, P.V.T, Writing ? review & editing, S.G.K, D.A.S and P.V.T. All authors have no conflicts of interest to declare.

Funding Information:
This work was supported by the Vikings’ Children Fund and Minnesota Medical Foundation to P.V.T., and NIH grants CA241627 and HL135895 to D.A.S.

Publisher Copyright:
© 2021 IBRO

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • TMEM35a/NACHO
  • inflammation
  • nicotinic acetylcholine receptor
  • pain
  • spinal transcriptome

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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