• Tony L Yaksh, Kelly A Eddinger, Shinichi Kokubu, Zhenping Wang, Anna DiNardo, Roshni Ramachandran, Yuelian Zhu, Yajun He, Fieke Weren, Daphne Quang, Shelle A Malkmus, Katherine Lansu, Wesley K Kroeze, Brian Eliceiri, Joanne J Steinauer, Peter W Schiller, Peter Gmeiner, Linda M Page, and Keith R Hildebrand.
• 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.) 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., W.K.K) Montreal Clinical Research Institute and the Department of Pharmacology and Physiology, University of Montreal, Quebec, Canada (P.W.S.) Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Germany (P.G.) Implantables Research and Technology, Medtronic, Inc., Restorative Therapies Group, Minneapolis, Minnesota (L.M.P., K.R.H.).
• Anesthesiology. 2019 Jul 1; 131 (1): 132147132-147.

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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