ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2002
Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers, 1 of them a synthesis that pooled it.
What it found
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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
103 citing papers in PubMed, 1 synthesis or guideline pooled it, 318 citations in OpenAlex.
- Progress in Pathological and Therapeutic Research of HIV-Related Neuropathic Pain.Cellular and molecular neurobiology · 2023Pooled it
- Methadone maintenance patients lack analgesic response to a cumulative intravenous dose of 32 mg of hydromorphone.Drug and alcohol dependence · 2021Trial
- Tramadol induces hormonal imbalance, histopathology, and altered ovarian gene expression in mice.Clinical and experimental reproductive medicine · 2026Article
- Involvement of endolysosome iron in HIV-1 gp120-, morphine-, and iron supplementation-induced disruption of the reactive species interactome and induction of neurotoxicity.Redox report : communications in free radical research · 2025Article
- TRPV1 channel antagonist capsazepine alleviates morphine tolerance and morphine-induced neurotoxicity by preventing mitochondrial damage and apoptosis: an in vivo and in vitro study.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Novel neurotherapeutic targets for substance use disorders: Neuroplasticity, neuroinflammation, gasotransmitters and non-canonical organ systems.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Mitochondrial Calcium Uniporter (MCU)-Mediated Calcium Overload in Psychoactive Drug Neurotoxicity: From Pathogenesis to Therapeutic Targets.International journal of molecular sciences · 2025Review
- Drug-Induced Cognitive Impairment.Drug safety · 2025Review
- Treadmill Exercise Training Ameliorates Apoptotic Cells and DNA Oxidation in the Cerebral Cortex of Rats Exposed to Chronic Ketamine Abuse.Addiction biology · 2025Article
- Nociplastic pain: controversy of the concept.The Korean journal of pain · 2025Review
- Morphine induces inflammatory responses via both TLR4 and cGAS-STING signaling pathways.Cytokine · 2024Article
- Differential Effect of Chronic Morphine on Neuronal Degeneration in Male vs. Female Mice.Pathophysiology : the official journal of the International Society for Pathophysiology · 2024Article
- Aspirin attenuates morphine antinociceptive tolerance in rats with diabetic neuropathy by inhibiting apoptosis in the dorsal root ganglia.Metabolic brain disease · 2023Article
- Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death.NeuroImmune pharmacology and therapeutics · 2023Article
- The effects of general anesthetics on mitochondrial structure and function in the developing brain.Frontiers in neurology · 2023Review
- Modifiable contributing factors to COVID-19: A comprehensive review.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2023Review
- The Use of Dexmedetomidine in Preterm Infants: A Single Academic Center Experience.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2023Article
- Metformin prevents morphine-induced apoptosis in rats with diabetic neuropathy: a possible mechanism for attenuating morphine tolerance.Naunyn-Schmiedeberg's archives of pharmacology · 2022Article
- Review
- TRESK Regulates Gm11874 to Induce Apoptosis of Spinal Cord Neurons via ATP5i Mediated Oxidative Stress and DNA Damage.Neurochemical research · 2021Article
43 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
4 authors at 1 institution in 1 country.
Funding
Abstract
Tolerance to the analgesic effect of an opioid is a pharmacological phenomenon that occurs after its prolonged administration. Activation of the NMDA receptor (NMDAR) has been implicated in the cellular mechanisms of opioid tolerance. However, activation of NMDARs can lead to neurotoxicity under many circumstances. Here we demonstrate that spinal neuronal apoptosis was induced in rats made tolerant to morphine administered through intrathecal boluses or continuous infusion. The apoptotic cells were predominantly located in the superficial spinal cord dorsal horn, and most apoptotic cells also expressed glutamic acid decarboxylase, a key enzyme for the synthesis of the inhibitory neurotransmitter GABA. Consistently, increased nociceptive sensitivity to heat stimulation was observed in these same rats. Mechanistically, the spinal glutamatergic activity modulated morphine-induced neuronal apoptosis, because pharmacological perturbation of the spinal glutamate transporter activity or coadministration of morphine with the NMDAR antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate affected both morphine tolerance and neuronal apoptosis. At the intracellular level, prolonged morphine administration resulted in an upregulation of the proapoptotic caspase-3 and Bax proteins but a downregulation of the antiapoptotic Bcl-2 protein in the spinal cord dorsal horn. Furthermore, coadministration with morphine of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (a pan-caspase inhibitor) or acetyl-aspartyl-glutamyl-valyl-aspart-1-aldehyde (a relatively selective caspase-3 inhibitor) blocked morphine-induced neuronal apoptosis. Blockade of the spinal caspase-like activity also partially prevented morphine tolerance and the associated increase in nociceptive sensitivity. These results indicate an opioid-induced neurotoxic consequence regulated by the NMDAR-caspase pathway, a mechanism that may have clinical implications in opioid therapy and substance abuse.
Indexed as
Identifiers
12196588PMC6757968W1535722786What 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.