Pain Medicine  |   July 2019
Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass: Role of Mas-related G Protein-coupled Receptor Signaling
Author Notes
  • 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., 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.); and Implantables Research and Technology, Medtronic, Inc., Restorative Therapies Group, Minneapolis, Minnesota (L.M.P., K.R.H.).
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    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
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  • Portions of this work were presented at the North American Neuromodulation Society meeting in Las Vegas, Nevada, January 11-14, 2018.
    Portions of this work were presented at the North American Neuromodulation Society meeting in Las Vegas, Nevada, January 11-14, 2018.×
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Article Information
Pain Medicine / Basic Science / Pain Medicine / Pharmacology / Opioid
Pain Medicine   |   July 2019
Mast Cell Degranulation and Fibroblast Activation in the Morphine-induced Spinal Mass: Role of Mas-related G Protein-coupled Receptor Signaling
Anesthesiology 7 2019, Vol.131, 132-147. doi:10.1097/ALN.0000000000002730
Anesthesiology 7 2019, Vol.131, 132-147. doi:10.1097/ALN.0000000000002730
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • The formation of intrathecal masses complicates the use of intrathecal opioid therapy for chronic pain

  • The degranulation of mast cells has been linked to intrathecal mass formation

What This Article Tells Us That Is New:

  • Using a guinea pig model, masses formed around intrathecal catheters when morphine was infused, and this mass formation was not prevented by opioid receptor blockade

  • Non-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 formation

  • Agents 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 (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.