Paper of the month 2024 >>

Paper of the month – December 2022 (Binshtok’s lab)

Binshtok’s lab: 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

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

J Clin Invest. 2022;132(15):e152635 (2022)

Lay summary:

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. We show that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of the nociceptive terminals and leads to inflammatory pain. Computational modelling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptive neurons. Targeting mTORC2 using a single injection of antisense oligonucleotide (ASO) against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we show that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, thus representing a new therapeutic target for inflammatory pain.

Figure 1. Summary – Inflammation leads to changes in the architecture of peripheral terminal endings of nociceptive (pain-related) neurons. These changes are sufficient to enhance the excitability of pain-related neurons, thus leading to inflammatory pain

Figure 2. A. High-resolution imaging of peripheral terminals of nociceptive neurons demonstrating changes in their structure occurring during the peak of inflammation-induced pain. B. Computational modeling of a nociceptive neuron shows that inflammation-induced changes in terminal architecture leads to a substantial increase of the output of the nociceptive neuron.

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