Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation

Rondon, Eric Schmidt; Wang, Zhenping; Malkmus, Shelle; Nardo, Anna Di; Hildebrand, Keith R.; Page, Linda M.; Yaksh, Tony L.

doi:10.1016/j.taap.2017.10.017

Cited by 15 publications

(18 citation statements)

References 75 publications

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“…These masses are not prevented by opiate receptor antagonism . The common feature of the agents resulting in such masses is their propensity to degranulate mast cells in an opiate receptor independent fashion . In the present studies, we demonstrate that DMT‐DALDA and morphine at comparable molar concentrations both produce a robust mast cell activation in the cromolyn‐sensitive intradermal flare model.…”

Section: Discussionsupporting

confidence: 48%

“…While systematic histopathology was not performed in these pharmacologic studies, we have previously observed that a 14‐day infusion of analgesic concentrations of morphine will yield such masses and an attendant motor dysfunction in guinea pigs (not seen in the present studies). In this regard, morphine interacts with Mas‐related G protein‐coupled receptors (MRGs), and mast cell degranulation is mediated in part by activation of this signaling cascade and that fentanyl, which does not activate MRGs , does not degranulate mast cells and has a low risk of producing spinal masses in animals and humans .…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Kokubu

Eddinger

Yamaguchi

et al. 2019

Neuromodulation: Technology at the Neural Interface

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Objectives DMT‐DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2; Dmt = 2′,6′‐dimethyltyrosine) is a selective mu opioid agonist. We sought to characterize efficacy, tolerance, dependence and side‐effect profile when given by continuous intrathecal infusion. Materials and Methods Adult male Sprague Dawley rats were prepared with chronic intrathecal catheters and osmotic mini‐pumps to deliver vehicle (saline), DMT‐DALDA or morphine. Hind paw thermal escape latencies were assessed. In addition, effects upon intraplantar formalin‐evoked flinching and withdrawal after 14 days of infusion were examined. The flare response after intradermal delivery was examined in the canine model. Results 1) Intrathecal infusion of 0.3 to 30 pmol/μL/hour of DMT‐DALDA or 37.5 nmol/μL/hour of morphine more than 7 or 14 days resulted in a dose‐dependent increase in thermal escape latency. The maximum antinociceptive effect was observed between 1 and 4 days after start of infusion with preserved cornea, blink, placing and stepping. By days 12 to 14, response latencies were below baseline. 2) On days 2 to 4 of DMT‐DALDA infusion, the pan opioid receptor antagonist naloxone (Nx), but not the delta‐preferring antagonist naltrindole, antagonized the analgesic effects. 3) Assessment of formalin flinching on day 1 following IT DMT‐DALDA Infusion showed significant analgesia in phases 1 and 2. On day 6 of infusion there was minimal effect, while on day 13, there was an increase in flinching. 4) On days 7 and 14 of infusion Nx resulted in prominent withdrawal signs indicating dependence and withdrawal. 5) Intradermal morphine and DMT‐DALDA both yield a naltrexone‐insensitive, cromolyn‐sensitive flare in the canine model at similar concentrations. Conclusions These data suggest that DMT‐DALDA is a potent, spinally active agonist with a propensity to produce tolerance dependence and mast cell degranulation. While it was equiactive to morphine in producing mast cell degranulation, it was >1000 fold more potent in producing analgesia, suggesting a possible lower risk in producing a spinal mass at equianalgesic doses.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Kokubu

Eddinger

Yamaguchi

et al. 2019

Neuromodulation: Technology at the Neural Interface

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“…In previous work we have shown in several models that the degranulating effects of morphine were not naloxone antagonized, but were prevented by the mast cell stabilizer, cromolyn. 12 In contrast to morphine, PZM21 had no effect upon mast cell degranulation. DMT-DALDA resulted in a significant degranulation as compared to control, but only at the highest concentration (10 μM) examined.…”

Section: Intrathecal Masses Constituted Of Local Collections Of Fibromentioning

confidence: 93%

“…These observations argue that these effects are not mediated by an opioid receptor and parallel the pharmacology of mast cell degranulation. 12 Meningeal mast cells are indeed degranulated in a naloxoneindependent fashion by morphine. 11 The role of mast cell degranulation in IT morphineinduced mass formation is supported by the observation that mast cell stabilizers could reduce the incidence/size of the intrathecal mass in dog.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…Thus, while there are data showing that histamine (acting through an H1 receptors) can increase fibroblast proliferation ( but see ) and migration (), the results observed with concurrent diphenhydramine dosing of all groups revealed that those animals receiving a continuous delivery displayed greater mass formation than those in the bolus paradigms. In canine studies, fentanyl and alfentanil, unlike morphine, do not degranulate mast cells or produce IT masses . Current work has emphasized the role of a family of Mas‐Related G‐Protein Coupled Receptors (MRGP‐r) in mediating opioid‐receptor‐independent degranulation of mast cells by morphine .…”

Section: Discussionmentioning

confidence: 99%

Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog

Hildebrand

Page

Billstrom

et al. 2019

Neuromodulation: Technology at the Neural Interface

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Background We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. Methods Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 μL/hour, or as a continuous infusion (25 mg/mL/20 μL/hour). Results With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross‐sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross‐sectional mass area (mm2) was: Saline: 0.7 mm2; x2: 1.8 mm2; x4: 2.7 mm2; x1: 2.7 mm2; x8: 4.2 mm2; Continuous: 8.1 mm2, with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. Conclusions Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.

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Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation

Cited by 15 publications

References 75 publications

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

Characterization of Analgesic Actions of the Chronic Intrathecal Infusion of H-Dmt-D-Arg-Phe-Lys-NH2 in Rat

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

Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog

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