mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation
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
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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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 2

Activation of mTORC2 engenders structural remodelling of nociceptive distal endings in epidermis.

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Activation of mTORC2 engenders structural remodelling of nociceptive dis...
A-443654 (20 μL of 8 mM, intraplantar) was injected in ControltdTom (A) and Rictor-cKOtdTom (B) mice, and glabrous skin from the injected paw was collected 24 hours later. Representative images of the low (top) and high (bottom) magnification of nociceptive fibers in the epidermis, acquired using confocal microscopy with AiryScan. A-443654 increases main fiber length in ControltdTom but not Rictor-cKOtdTom mice (C, n = 5 mice per group). Similarly, A-443654 increases the number of branches per fiber in ControltdTom but not Rictor-cKOtdTom mice (D, n = 5 mice per group). ControltdTom (E) and Rictor-cKOtdTom (F) mice were injected with CFA (intraplantar), and glabrous skin from the injected paw was collected at day 1, day 3, day 7, and day 14 after injection. CFA increases main fiber length in ControltdTom but not Rictor-cKOtdTom mice at day 1 after CFA (G, n = 4–5 per group). Similarly, CFA increases the number of branches per fiber in ControltdTom but not Rictor-cKOtdTom mice (H, n = 4–5 per group). Statistics are based on 2-way ANOVA followed by Bonferroni’s post hoc comparison. All data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 20 μm.