ArticleCellular and molecular neurobiology2022
Morphine and Fentanyl Repeated Administration Induces Different Levels of NLRP3-Dependent Pyroptosis in the Dorsal Raphe Nucleus of Male Rats via Cell-Specific Activation of TLR4 and Opioid Receptors.
Article in Cellular and molecular neurobiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 64 citations in OpenAlex.
- Minocycline attenuates oxycodone-induced positive subjective responses in non-dependent, recreational opioid users.Pharmacology, biochemistry, and behavior · 2021Trial
- The neuroimmune-glutamate hypothesis of addiction.Neuroscience and biobehavioral reviews · 2026Review
- S100A11 regulates microglial inflammatory response in neuropathic pain via H3K27ac-TFEB-mitochondrial autophagy axis.The journal of headache and pain · 2026Article
- Non-apoptotic Regulated Cell Death Mechanisms in Sepsis and their Therapeutic Potential.Inflammation · 2026Review
- Analgesic efficacy in women and men with cancer pain, treated with strong opioids: are there differences?BMJ oncology · 2026Article
- Epigenetic mechanisms of HIV and opioid-induced neuropathology: Potential therapies and interventions.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Comparative effects of fentanyl, morphine, and hydromorphone on postoperative delirium and outcomes after cardiac surgery: a propensity score-matched cohort study.Scientific reports · 2025Article
- NLRP3 inflammasome: a key driver of neuroinflammation and a novel therapeutic target for neuropathic pain.Anesthesia and pain medicine · 2025Review
- Astrocytes and Astrocyte-Derived Extracellular Conduits in Opiate-Mediated Neurological Disorders.Cells · 2025Review
- Mechanism of Microbiota-Gut-Brain in Perimenopausal Depression: An Inflammatory Perspective.Expert reviews in molecular medicine · 2025Review
- Differential effects of fentanyl compared to morphine on neuroinflammatory signaling in the brain in EcoHIV-infected mice.Journal of neurovirology · 2025Article
- NLRP3 Inflammasome: A New Target for the Treatment of CVD and Depression Comorbidity.Mediators of inflammation · 2025Review
- Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development.Frontiers in neuroscience · 2025Review
- Neuroimmune modulatory effects of the NLRP3 inflammasome: the role of sex and living environment in brain affecting conditions.Frontiers in immunology · 2025Review
- The effect of cannabinoid type 2 receptor agonist on morphine tolerance.IBRO neuroscience reports · 2024Review
- Microglia in neuroimmunopharmacology and drug addiction.Molecular psychiatry · 2024Review
- Role of pyroptosis in the pathogenesis of various neurological diseases.Brain, behavior, and immunity · 2024Review
- Neuroimmune modulators as novel pharmacotherapies for substance use disorders.Brain, behavior, & immunity - health · 2024Article
- Methadone Requires the Co-Activation of μ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.International journal of molecular sciences · 2024Article
- Zingerone Alleviates Morphine Tolerance and Dependence in Mice by Reducing Oxidative Stress-Mediated NLRP3 Inflammasome Activation.Neurochemical research · 2024Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.
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