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 6

Antisense oligonucleotide targeting Rictor alleviates inflammatory pain.

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Antisense oligonucleotide targeting Rictor alleviates inflammatory pain....
(A) Schematic shows experimental design of Rictor antisense oligonucleotide (Rictor-ASO) treatment (s.c.). (B) Western blots and quantification show that Rictor-ASO reduces the levels of Rictor and p-Akt (Ser473) (n = 4–5 mice per group, Student’s t test, 2 tailed). ControltdTom mice were injected with Control- (C) and Rictor-ASO (D) (100 mg/kg s.c.) 2 weeks prior to intraplantar injection of CFA, and the 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 were acquired using confocal microscopy with AiryScan. Rictor-ASO rescued CFA-induced increases in main fiber length (E, n = 4 mice per group) and increases in the number of branches per fiber (F, n = 4 mice per group). No differences between Control-ASO and Rictor-ASO mice after CFA intraplantar injection in the number of fibers (G), branch length (H), or distance to branching point (I). Treatment with Rictor-ASO alleviates hypersensitivity induced by CFA (J, von Frey; K, radiant heat paw withdrawal) and γ-carrageenan (L, von Frey; M, radiant heat paw withdrawal). Two-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 bar: 20 μm.