ArticleNeuroscience2013
Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice.
Article in Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- BTP2, a store-operated calcium channel inhibitor, attenuates morphine antinociceptive tolerance in rats.Frontiers in neuroscience · 2026Article
- Molecular Mechanisms Underlying Burn-Injury Induced Pain: From Inflammation to Epigenetics.Military medicine · 2025Review
- Multi-dimensional Multi-omics Integrative Study to Identify Target Genes for Ischemic Stroke and Related Chronic Pain.Cellular and molecular neurobiology · 2025Article
- UltramicronizedCurrent neuropharmacology · 2024Article
- Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.International journal of molecular sciences · 2023Review
- Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling.Molecular psychiatry · 2023Article
- Opioid Modulation of the Gut-Brain Axis in Opioid-Associated Comorbidities.Cold Spring Harbor perspectives in medicine · 2021Review
- Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.Pharmacology research & perspectives · 2021Review
- Morphine produces better thermal analgesia in young Huntington mice and are associated with less neuroinflammation in spinal cord.Journal of the Chinese Medical Association : JCMA · 2021Article
- Morphine promotes microglial activation by upregulating the EGFR/ERK signaling pathway.PloS one · 2021Article
- Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The analgesic effect and possible mechanisms by which koumine alters type II collagen-induced arthritis in rats.Journal of natural medicines · 2019Article
- Magnetic field distribution modulation of intrathecal delivered ketorolac iron-oxide nanoparticle conjugates produce excellent analgesia for chronic inflammatory pain.Journal of nanobiotechnology · 2018Article
- Cyclosporin A attenuating morphine tolerance through inhibiting NO/ERK signaling pathway in human glioblastoma cell line: the involvement of calcineurin.EXCLI journal · 2018Article
- Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor.Neurotoxicity research · 2017Article
- Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.Journal of neuroinflammation · 2016Article
- The dark side of opioids in pain management: basic science explains clinical observation.Pain reports · 2016Article
- Curcumin ameliorates neuropathic pain by down-regulating spinal IL-1β via suppressing astroglial NALP1 inflammasome and JAK2-STAT3 signalling.Scientific reports · 2016Article
- The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.BMC genomics · 2016Article
- Contribution of adrenomedullin to the switch of G protein-coupled μ-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats.British journal of pharmacology · 2016Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Accumulating evidence indicates that activation of spinal cord astrocytes contributes importantly to nerve injury and inflammation-induced persistent pain and chronic opioid-induced antinociceptive tolerance. Phosphorylation of extracellular signal-regulated kinase (pERK) and induction of interleukin-1 beta (IL-1β) in spinal astrocytes have been implicated in astrocytes-mediated pain. Tissue plasminogen activator (tPA) is a serine protease that has been extensively used to treat stroke. We examined the potential involvement of tPA in chronic opioid-induced antinociceptive tolerance and activation of spinal astrocytes using tPA knockout (tPA(-/-)) mice and astrocyte cultures. tPA(-/-) mice exhibited unaltered nociceptive pain and morphine-induced acute analgesia. However, the antinociceptive tolerance, induced by chronic morphine (10mg/kg/day, s.c.), is abrogated in tPA(-/-) mice. Chronic morphine induces tPA expression in glial fibrillary acidic protein (GFAP)-expressing spinal cord astrocytes. Chronic morphine also increases IL-1β expression in GFAP-expressing astrocytes, which is abolished in tPA-deficient mice. In cultured astrocytes, morphine treatment increases tPA, IL-1β, and pERK expression, and the increased IL-1β and pERK expression is abolished in tPA-deficient astrocytes. tPA is also sufficient to induce IL-1β and pERK expression in astrocyte cultures. Intrathecal injection of tPA results in up-regulation of GFAP and pERK in spinal astrocytes but not up-regulation of ionized calcium binding adapter molecule 1 in spinal microglia. Finally, intrathecal tPA elicits persistent mechanical allodynia, which is inhibited by the astroglial toxin alpha-amino adipate and the MEK (ERK kinase) inhibitor U0126. Collectively, these data suggest an important role of tPA in regulating astrocytic signaling, pain hypersensitivity, and morphine tolerance.
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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.