Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass: Role of Mas-related G Protein-coupled Receptor Signaling

• Published in: Anesthesiology (Philadelphia) 2019-07, Vol.131 (1), p.132-147
• Main Authors: Yaksh, Tony L, Eddinger, Kelly A, Kokubu, Shinichi, Wang, Zhenping, DiNardo, Anna, Ramachandran, Roshni, Zhu, Yuelian, He, Yajun, Weren, Fieke, Quang, Daphne, Malkmus, Shelle A, Lansu, Katherine, Kroeze, Wesley K, Eliceiri, Brian, Steinauer, Joanne J, Schiller, Peter W, Gmeiner, Peter, Page, Linda M, Hildebrand, Keith R
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; Cell Degranulation - drug effects; Fibroblasts - drug effects; Guinea Pigs; Humans; Infusions, Spinal; Male; Mast Cells - drug effects; Models, Animal; Morphine - administration & dosage; Morphine - pharmacology; Receptors, G-Protein-Coupled - physiology; Signal Transduction - physiology; Spine - drug effects
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000002730

WHAT WE ALREADY KNOW ABOUT THIS TOPICThe formation of intrathecal masses complicates the use of intrathecal opioid therapy for chronic painThe degranulation of mast cells has been linked to intrathecal mass formation WHAT THIS ARTICLE TELLS US THAT IS NEWUsing a guinea pig model, masses formed around intrathecal catheters when morphine was infused, and this mass formation was not prevented by opioid receptor blockadeNon-opioid receptor mediated stimulation of Mas-related G protein-coupled receptor appeared to be mechanism responsible for mast cell degranulation, fibroblast proliferation and ultimately mass formationAgents not activating Mas-related genes at analgesic doses did not produce masses BACKGROUND:As 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? METHODS:In 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. RESULTS:Intrathecal 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 (medianinterquartile range, 0 to 4 scale), were produced by morphine (2.32.0 to 3.5) and morphine plus naltrexone (2.51.4 to 3.1), but not vehicle (1.21.1 to 1.5), DMT-DALDA (1.00.6 to 1.3), or PZM21 (0.50.4 to 0.8). Morphine in a naloxone-insensitive fashion, but not PZM21 or DMT-