Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery

Kokubu, Shinichi; Eddinger, Kelly A.; Nguyen, Thi M.‐D.; Huerta-Esquivel, Lena Libertad; Yamaguchi, Shigeki; Schiller, Peter W.; Yaksh, Tony L.

doi:10.1515/sjpain-2018-0120

Cited by 4 publications

(4 citation statements)

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“…15 Conversely, PZM21, developed as a biased mu-opioid ligand, fails to activate MRGs and, as we show here, will not degranulate mast cells or produce a spinal mass. Alternatively, mu opioid ligands such as the dermorphin-derived peptides (DMT-DALDA) are extremely potent after intrathecal delivery, 16,17 and while they degranulate mast cells, we show here that the low concentrations required to produce mu opiate receptor mediated analgesia fails to produce a mass in vivo. 18,19…”

Section: Introductionmentioning

confidence: 75%

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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Section: Introductionmentioning

confidence: 75%

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

et al. 2019

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“…En este estudio los animales de experimentación se trataron con morfina intratecal durante cinco días antes de la administración de DMT-DALDA, y se observó que el efecto analgésico no se redujo como ocurre con la morfina como resultado del desarrollo de la tolerancia. Esta tolerancia asimétrica es interesante, ya que podría indicar que el péptido tiene un mejor efecto intrínseco en comparación con la morfina y abre una línea prometedora de investigación (16).…”

Section: Acción Analgésica Medularunclassified

Factores clave que afectan a la biodisponibilidad de los opioides sobre la médula espinal en el manejo del dolor agudo

Bujedo¹

2019

Rev. Soc. Esp. Dolor.

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“…In companion work we systematically examined the antinociceptive effects of the bolus delivery of a family of peptides built on the endogenous mu opioid peptide: dermorphin. In this allied work we observed that one of the analogues, DMT‐DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2), which displays a high affinity at the mu receptor (K i μ = 0.143 65 nM) and high receptor selectivity for mu vs. delta and kappa opioid receptors (K i δ /K i μ > 10,000 and K i κ /K i μ > 100) , and an extraordinary potency in blocking a spinal reflex (the tail‐flick) , hind paw withdrawal to a thermal stimulus and a reduction in formalin‐evoked flinching after bolus IT administration.…”

Section: Introductionmentioning

confidence: 99%

“…Of interest, several of these peptides carry a net positive charge at physiologic pH and are thus very hydrophilic, which suggests a long residency time in the intrathecal space, a property supporting an extended duration of action after intrathecal delivery. Indeed, following bolus delivery of equiactive doses, durations of action comparable to morphine were observed . To further characterize, the spinal actions of DMT‐DALDA and, for comparison, morphine, we undertook the following studies: 1) systematic time and concentration‐effect curves for chronically infused intrathecal DMT‐DALDA/morphine; 2) receptor pharmacology of spinally infused DMT‐DALDA/morphine using Nx (a pan‐opiate antagonist) and naltrindole (Ntd; a delta receptor preferring antagonist); and 3) examining the ability of DMT‐DALDa and morphine to produce mast cell degranulation, a mechanism proposed to mediate the opiate receptor independent generation of an intrathecal mass using the naltrexone‐insensitive, cutaneous flare observed after intradermal delivery .…”

Section: Introductionmentioning

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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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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Characterization of the antinociceptive effects of intrathecal DALDA peptides following bolus intrathecal delivery

Cited by 4 publications

References 43 publications

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

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

Factores clave que afectan a la biodisponibilidad de los opioides sobre la médula espinal en el manejo del dolor agudo

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

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