ArticlePain2013
mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK.
Article in Pain, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
59 citing papers in PubMed, 99 citations in OpenAlex.
- Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study.International journal of colorectal disease · 2018Trial
- Lanthionine synthetase C-like protein 1 (LanCL1): a therapeutic target for neuropathic pain.Pain · 2026Article
- Diet-induced obesity exacerbates and prolongs postoperative pain via peripheral DRG transcriptional changes in rats.Journal of dental anesthesia and pain medicine · 2026Article
- SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling.Scientific reports · 2025Article
- Cold receptor TRPM8 as a target for migraine-associated pain and affective comorbidities.The journal of headache and pain · 2025Article
- Metformin for low back pain: Study protocol for a randomised, double-blind, placebo-controlled trial.Osteoarthritis and cartilage open · 2025Article
- Guardians of Sensation: Evaluating Metformin's Power Against Chemotherapy-Induced Neuropathy.International journal of breast cancer · 2025Article
- A nociceptor-specific RNAi screen inPeerJ · 2025Article
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- Anandamide Modulates Thermal Avoidance in Caenorhabditis elegans Through Vanilloid and Cannabinoid Receptor Interplay.Neurochemical research · 2024Article
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- Metformin inhibits spontaneous excitatory postsynaptic currents in spinal dorsal cord neurons from paclitaxel-treated rats.Frontiers in synaptic neuroscience · 2023Article
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- Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin.International journal of molecular sciences · 2022Article
- A role for translational regulation by S6 kinase and a downstream target in inflammatory pain.British journal of pharmacology · 2021Article
- Roles of AMPK and Its Downstream Signals in Pain Regulation.Life (Basel, Switzerland) · 2021Review
- Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system.Expert review of neurotherapeutics · 2021Article
- Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain.Pharmacological reviews · 2021Review
- RNA control in pain: Blame it on the messenger.Wiley interdisciplinary reviews. RNA · 2019Review
- Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are extensively used as immunosuppressants to prevent transplant rejection and in treatment of certain cancers. In patients, chronic treatment with rapamycin or its analogues (rapalogues) has been reported to lead to sensory hypersensitivity and pain conditions via an unknown mechanism. Here, we show that pharmacological or genetic inhibition of mTORC1 activates the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop. As a result, increased ERK activity induces sensory neuron sensitization, mechanical hypersensitivity, and spontaneous pain. The clinically available adenosine monophosphate-activated protein kinase activator, metformin, which is an antidiabetic drug, prevents rapamycin-induced ERK activation and the development of mechanical hypersensitivity and spontaneous pain. Taken together, our findings demonstrate that activation of the ERK pathway in sensory neurons as a consequence of mTORC1 inhibition leads to the development of pain. Importantly, this effect is abolished by co-treatment with metformin, thus providing a potential treatment option for rapalogue-evoked pain. Our findings highlight the physiological relevance of feedback signaling through mTORC1 inhibition and have important implications for development of pain therapeutics that target the mTOR pathway.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.