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 4

mTORC2 mediates inflammation-induced structural changes in nociceptive fibers in cornea and promotes pain.

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mTORC2 mediates inflammation-induced structural changes in nociceptive f...
ControltdTom and Rictor-cKOtdTom mice were subjected to UV irradiation (22 minutes, 450 mJ/cm2), and cornea tissue was extracted 24 hours later. Confocal imaging shows that UV-induced inflammation promotes structural changes in control mice (A), but not in Rictor-deficient animals (B). UV induces changes in ControltdTom but not in Rictor-cKOtdTom mice in main fiber length (C) and the number of branches per fiber (D). No differences were seen between naive and UV-irradiated mice in the number of fibers (E), branch length (F), or distance to branching point (G) (n = 5 animals per group for A–G, 2-way ANOVA followed by Bonferroni’s post hoc comparison). Twenty-four hours after UV irradiation, capsaicin (10 μl of 1 μM) was applied unilaterally onto the eye (H) and the numbers of wipes (I) and blinks (J) within 5 minutes after administration were quantified (2-way ANOVA mixed effects model 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: 10 μm.