mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation
Calvin Wong, … , Alexander M. Binshtok, Arkady Khoutorsky
Calvin Wong, … , Alexander M. Binshtok, Arkady Khoutorsky
Published May 17, 2022
Citation Information: J Clin Invest. 2022;132(15):e152635. https://doi.org/10.1172/JCI152635.
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Research Article Neuroscience

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

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.

Authors

Calvin Wong, Omer Barkai, Feng Wang, Carolina Thörn 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 Séguéla, Yves De Koninck, Alfredo Ribeiro-da-Silva, Alexander M. Binshtok, Arkady Khoutorsky

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Figure 3

mTORC2 promotes structural changes in distal nociceptive endings and pain via modulation of actin dynamics.

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mTORC2 promotes structural changes in distal nociceptive endings and pai...
ControltdTom mice were injected with A-443654 alone (intraplantar, 20 μL, 8 mM) and together with an inhibitor of Rac1 (NSC23766, intraplantar, 10 μL, 10 mM, 15 minutes prior to A-443654) and CDC42 (ML141, intraplantar, 10 μL, 50 μM, 15 minutes prior to A-443654). Imaging of tissue collected 24 hours after A-443654 injection revealed that Rac1/CDC42 inhibitors prevent A-443654–induced structural changes in nociceptive endings in epidermis (A). Quantification shows that NSC23766/ML141 block A-443654–induced increase in main fiber length (B, top, n = 5 mice per group) and the number of branches per fiber (B, bottom). NSC23766/ML141 also alleviated A-443654–induced hypersensitivity (C and D). (E) Mice were injected with CFA (intraplantar) in the absence and presence of NSC23766/ML141 (intraplantar, 15 minutes prior to CFA), and the glabrous skin from the injected paw was fixed 24 hours later and imaged. NSC23766/ML141 blocked CFA-induced increase in main fiber length (F, top, n = 5 mice per group) and the number of branches per fiber (F, bottom). NSC23766/ML141 also alleviated CFA-induced hypersensitivity (G and H). One-way ANOVA followed by Bonferroni’s post hoc comparison (B and F); 2-way ANOVA followed by Bonferroni’s post hoc comparison (C, D, G, and H). All data are represented as mean ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 20 μm.