MTORC2 Mediates Structural Plasticity in Distal Nociceptive Endings That Contributes to Pain Hypersensitivity Following Inflammation

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2022 May 17

PMID 35579957

Authors

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

Affiliations

Soon will be listed here.

Abstract

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 long-lasting 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.

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