Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass

Author:

Yaksh Tony L.1,Eddinger Kelly A.1,Kokubu Shinichi1,Wang Zhenping1,DiNardo Anna1,Ramachandran Roshni1,Zhu Yuelian1,He Yajun1,Weren Fieke1,Quang Daphne1,Malkmus Shelle A.1,Lansu Katherine1,Kroeze Wesley K.1,Eliceiri Brian1,Steinauer Joanne J.1,Schiller Peter W.1,Gmeiner Peter1,Page Linda M.1,Hildebrand Keith R.1

Affiliation:

1. From the Laboratory of Anesthesiology Research, Department of Anesthesiology (T.L.Y., K.A.E., S.K., R.R., Y.Z., Y.H., F.W., D.Q., S.A.M., J.J.S.), Department of Dermatology (Z.W., A.D.), and Division of Trauma, Department of Surgery (B.P.E.), University of California, San Diego, California; the Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (K.L.

Abstract

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New 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 (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. Conclusions Opiates 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

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