ArticleThe Journal of clinical investigation2014
Opioid receptor-triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 1 of them a synthesis that pooled it.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
101 citing papers in PubMed, 1 synthesis or guideline pooled it, 162 citations in OpenAlex.
- Different genes may be involved in distal and local sensitization: A genome-wide gene-based association study and meta-analysis.European journal of pain (London, England) · 2022Pooled it
- Dual CCR2/CCR5 Antagonism with Cenicriviroc Alleviates Nerve Injury-Induced Hypersensitivity and Prevents Morphine Tolerancevia Modulation of Neuroimmune Signaling.Cellular and molecular neurobiology · 2026Article
- The role of nucleus accumbens dopamine signaling in the development of morphine tolerance in neuropathic pain.The Korean journal of pain · 2026Article
- Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance.Pain reports · 2025Article
- Morphine-induced hyperalgesia impacts small extracellular vesicle microRNA composition and function.The Journal of pharmacology and experimental therapeutics · 2025Article
- Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain.Brain : a journal of neurology · 2025Article
- iTRAQ proteomic analysis of the anterior insula in morphine-induced conditioned place preference rats with high-frequency deep brain stimulation intervention.Addiction biology · 2025Article
- Pharmacological Perspective on the Neurobiology of PI3K-Akt-mTOR Signalling in Opioid Dependence.CNS & neurological disorders drug targets · 2025Review
- Morphine-induced hyperalgesia impacts small extracellular vesicle miRNA composition and function.bioRxiv : the preprint server for biology · 2024Article
- Astrocytic pyruvate dehydrogenase kinase-lactic acid axis involvement in glia-neuron crosstalk contributes to morphine-induced hyperalgesia in mice.Fundamental research · 2024Article
- Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.Scientific reports · 2024Article
- UltramicronizedCurrent neuropharmacology · 2024Article
- Upregulation of lysine-specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation-dependent production of TNF-α in the dorsal root ganglia and spinal dorsal horn in rats.CNS neuroscience & therapeutics · 2023Article
- A sensory neuron-specific long non-coding RNA reduces neuropathic pain by rescuing KCNN1 expression.Brain : a journal of neurology · 2023Article
- Antimicrobial therapies for chronic pain (part 1): analgesic mechanisms.The Korean journal of pain · 2023Review
- Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.Neural regeneration research · 2023Review
- Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia.The Journal of clinical investigation · 2022Article
- Article
- Metformin prevents morphine-induced apoptosis in rats with diabetic neuropathy: a possible mechanism for attenuating morphine tolerance.Naunyn-Schmiedeberg's archives of pharmacology · 2022Article
- Activation of Double-Stranded RNA-Activated Protein Kinase in the Dorsal Root Ganglia and Spinal Dorsal Horn Regulates Neuropathic Pain Following Peripheral Nerve Injury in Rats.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
41 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through μ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the μ opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management.
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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.