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mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK

Ohannes K Melemedjian1, Arkady Khoutorsky, Robert E Sorge

  • 1Department of Pharmacology, University of Arizona, Tucson, AZ, USA.

Pain
|April 24, 2013
PubMed

Insights

Mammalian target of rapamycin complex 1 (mTORC1) inhibitors cause pain by activating the ERK pathway in sensory neurons. Metformin, an antidiabetic drug, prevents this pain by inhibiting ERK activation, offering a potential therapeutic strategy.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are crucial in immunosuppression and cancer therapy.
  • Chronic use of mTORC1 inhibitors like rapamycin can induce pain and sensory hypersensitivity through unknown mechanisms.

Purpose of the Study:

  • To elucidate the mechanism by which mTORC1 inhibition leads to pain.
  • To investigate the role of the extracellular signal-regulated kinase (ERK) pathway in sensory neurons.
  • To evaluate metformin as a potential therapeutic agent for rapamycin-induced pain.

Main Methods:

  • Pharmacological and genetic inhibition of mTORC1 in sensory neurons.
  • Analysis of the S6K1 to insulin receptor substrate 1 negative feedback loop.
  • Assessment of ERK pathway activation and its downstream effects on sensory neuron sensitization and pain behaviors.
  • In vivo studies using metformin co-treatment.

Main Results:

  • mTORC1 inhibition activates the ERK pathway in sensory neurons by suppressing the S6K1-IRS1 feedback loop.
  • Increased ERK activity in sensory neurons causes mechanical hypersensitivity and spontaneous pain.
  • Metformin prevents rapamycin-induced ERK activation and associated pain behaviors.

Conclusions:

  • Activation of the ERK pathway in sensory neurons is a key mechanism underlying mTORC1 inhibitor-induced pain.
  • Metformin effectively abolishes rapamycin-evoked pain, suggesting its potential as a co-treatment.
  • These findings offer insights into pain therapeutics targeting the mTOR pathway.

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