mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation

Calvin Wong, Omer Barkai, Feng Wang, Carolina Thorn Perez, Shaya Lev, Weihua Cai, Shannon Tansley, Noosha Yousefpour, Mehdi Hooshmandi, Kevin C. Lister, Mariam Latif, A. Claudio Cuello, Masha Prager-Khoutorsky, Jeffrey S. Mogil, Philippe Seguela, Yves De Koninck, Alfredo Ribeiro-Da-Silva, Alexander M. Binshtok*, Arkady Khoutorsky

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused longlasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.

Original languageEnglish
Article numbere152635
Pages (from-to)1-50
JournalJournal of Clinical Investigation
Issue number15
StatePublished - 22 Aug 2022

Bibliographical note

Funding Information:
We thank John N. Wood for providing Nav1.8Cre mice. This study was supported by the Canadian Institutes of Health Research (CIHR) (PJT-162412) and the Quebec Pain Research Network (QPRN) (to AK), the Israeli Science Foundation (grant agreement 1470/17), the CIHR, the International Development Research Centre (IDRC), the Azrieli Foundation (grant agreement 2545/18), the Deutsch-Israelische Projectkooperation Program of the Deutsche Forschungsgemeinschaft (grant agreement B.I. 1665/1-1ZI1172/12-1), and the Sessile and Seymour Alpert Chair in Pain Research (to AMB). The study was also supported by the Zavalkoff Family Foundation’s Brain@McGill and The Gail Asper Family Foundation IMRIC/Hebrew University (to AK and AMB). CW was supported by a Louise and Alan Edwards Foundation fellowship.

Publisher Copyright:
© 2022 American Society for Clinical Investigation. All rights reserved.


  • animal cell
  • animal experiment
  • animal tissue
  • article
  • computer model
  • controlled study
  • epidermis
  • excitability
  • gene deletion
  • hyperalgesia
  • hypersensitivity
  • inflammation
  • inflammatory pain
  • male
  • mouse
  • mouse model
  • nerve ending
  • neuroscience
  • nonhuman
  • pain receptor
  • signal transduction
  • antisense oligonucleotide
  • endogenous compound
  • mammalian target of rapamycin complex 2
  • rapamycin-insensitive companion of mTOR
  • regulator protein


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