ArticleAnesthesiology2019
Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass: Role of Mas-related G Protein-coupled Receptor Signaling.
Article in Anesthesiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review.Journal of neuroinflammation · 2020Pooled it
- Efficacy of Continuous Intrathecal Infusion Trialing with a Mixture of Fentanyl and Bupivacaine in Chronic Low Back Pain Patients.Pain medicine (Malden, Mass.) · 2023Trial
- OPRM1/MRGPRX1 heterodimers drive opioid-induced itch through a peripheral mechanism.Journal of biomedical science · 2026Article
- Opioids regulate the functional state of immune cells and reduce inflammatory cardiac injury: Role of opioid receptors, MRGPRX2, and TLR4.Journal of biomedical research · 2026Article
- Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.Science advances · 2024Article
- Mast cells: a double-edged sword in inflammation and fibrosis.Frontiers in cell and developmental biology · 2024Review
- UltramicronizedBiomolecules · 2023Article
- Τhe Effect of Opioid Administration on Cytologic and Histopathologic Diagnosis of Canine Cutaneous Mast Cell Tumors Treated by Surgical Excision.Veterinary sciences · 2022Article
- Intrathecal Drug Delivery: Advances and Applications in the Management of Chronic Pain Patient.Frontiers in pain research (Lausanne, Switzerland) · 2022Review
- Targeted Drug Delivery for Chronic Nonmalignant Pain: Longitudinal Data From the Product Surveillance Registry.Neuromodulation : journal of the International Neuromodulation Society · 2021Article
- Review
- Ligands and Signaling of Mas-Related G Protein-Coupled Receptor-X2 in Mast Cell Activation.Reviews of physiology, biochemistry and pharmacology · 2021Article
- Biased Opioid Ligands.Molecules (Basel, Switzerland) · 2020Review
- The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.Nature communications · 2020Article
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Authors and funding
19 authors at 1 institution in 3 countries.
Funding
Abstract
backgroundAs the meningeally derived, fibroblast-rich, mass-produced by intrathecal morphine infusion is not produced by all opiates, but reduced by mast cell stabilizers, the authors hypothesized a role for meningeal mast cell/fibroblast activation. Using the guinea pig, the authors asked: (1) Are intrathecal morphine masses blocked by opiate antagonism?; (2) Do opioid agonists not producing mast cell degranulation or fibroblast activation produce masses?; and (3) Do masses covary with Mas-related G protein-coupled receptor signaling thought to mediate mast cell degranulation?
methodsIn adult male guinea pigs (N = 66), lumbar intrathecal catheters connected to osmotic minipumps (14 days; 0.5 µl/h) were placed to deliver saline or equianalgesic concentrations of morphine sulfate (33 nmol/h), 2',6'-dimethyl tyrosine-(Tyr-D-Arg-Phe-Lys-NH2) (abbreviated as DMT-DALDA; 10 pmol/h; μ agonist) or PZM21 (27 nmol/h; biased μ agonist). A second pump delivered subcutaneous naltrexone (25 µg/h) in some animals. After 14 to 16 days, animals were anesthetized and perfusion-fixed. Drug effects on degranulation of human cultured mast cells, mouse embryonic fibroblast activation/migration/collagen formation, and Mas-related G protein-coupled receptor activation (PRESTO-Tango assays) were determined.
resultsIntrathecal infusion of morphine, DMT-DALDA or PZM21, but not saline, comparably increased thermal thresholds for 7 days. Spinal masses proximal to catheter tip, composed of fibroblast/collagen type I (median: interquartile range, 0 to 4 scale), were produced by morphine (2.3: 2.0 to 3.5) and morphine plus naltrexone (2.5: 1.4 to 3.1), but not vehicle (1.2: 1.1 to 1.5), DMT-DALDA (1.0: 0.6 to 1.3), or PZM21 (0.5: 0.4 to 0.8). Morphine in a naloxone-insensitive fashion, but not PZM21 or DMT-DALDA, resulted in mast cell degranulation and fibroblast proliferation/collagen formation. Morphine-induced fibroblast proliferation, as mast cell degranulation, is blocked by cromolyn. Mas-related G protein-coupled receptor activation was produced by morphine and TAN67 (∂-opioid agonist), but not by PZM21, TRV130 (mu biased ligand), or DMT-DALDA.
conclusionsOpiates that activate Mas-related G protein-coupled receptor will degranulate mast cells, activate fibroblasts, and result in intrathecal mass formation. Results suggest a mechanistically rational path forward to safer intrathecal opioid therapeutics.
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