Direct effect of remifentanil and glycine contained in Ultiva® on nociceptive transmission in the spinal cord: In vivo and slice patch clamp analyses

Makoto Sumie, Hiroaki Shiokawa, Ken Yamaura, Yuji Karashima, Sumio Hoka, Megumu Yoshimura

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Background: Ultiva® is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva® is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva® provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva® contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva® potentially complicates its effects. We examined how Ultiva1 directly affects nociceptive transmission in the spinal cord. Methods: We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva® onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli. Results: Bath application of Ultiva® hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva®. Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva®-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva®-induced currents demonstrated a specific equilibrium potential similar to glycine. Conclusions: We found that intrathecal administration of Ultiva1 to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva1-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous administrations.

元の言語英語
記事番号e0147339
ジャーナルPloS one
11
発行部数1
DOI
出版物ステータス出版済み - 1 1 2016

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Clamping devices
glycine (amino acid)
spinal cord
Glycine
Spinal Cord
neurons
narcotics
membrane potential
Substantia Gelatinosa
Neurons
receptors
antagonists
strychnine
naloxone
Membrane Potentials
Glycine Receptors
analgesics
aspartic acid
analgesia
neurotransmitters

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

これを引用

Direct effect of remifentanil and glycine contained in Ultiva® on nociceptive transmission in the spinal cord : In vivo and slice patch clamp analyses. / Sumie, Makoto; Shiokawa, Hiroaki; Yamaura, Ken; Karashima, Yuji; Hoka, Sumio; Yoshimura, Megumu.

:: PloS one, 巻 11, 番号 1, e0147339, 01.01.2016.

研究成果: ジャーナルへの寄稿記事

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title = "Direct effect of remifentanil and glycine contained in Ultiva{\circledR} on nociceptive transmission in the spinal cord: In vivo and slice patch clamp analyses",
abstract = "Background: Ultiva{\circledR} is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva{\circledR} is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva{\circledR} provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva{\circledR} contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva{\circledR} potentially complicates its effects. We examined how Ultiva1 directly affects nociceptive transmission in the spinal cord. Methods: We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva{\circledR} onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli. Results: Bath application of Ultiva{\circledR} hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva{\circledR}. Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva{\circledR}-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva{\circledR}-induced currents demonstrated a specific equilibrium potential similar to glycine. Conclusions: We found that intrathecal administration of Ultiva1 to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva1-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva{\circledR} between intrathecal and intravenous administrations.",
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T1 - Direct effect of remifentanil and glycine contained in Ultiva® on nociceptive transmission in the spinal cord

T2 - In vivo and slice patch clamp analyses

AU - Sumie, Makoto

AU - Shiokawa, Hiroaki

AU - Yamaura, Ken

AU - Karashima, Yuji

AU - Hoka, Sumio

AU - Yoshimura, Megumu

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AB - Background: Ultiva® is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting μ-opioid receptor agonist. Ultiva® is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva® provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva® contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva® potentially complicates its effects. We examined how Ultiva1 directly affects nociceptive transmission in the spinal cord. Methods: We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva® onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli. Results: Bath application of Ultiva® hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva®. Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva®-induced outward currents and suppression of mEPSCs were not inhibited by the μ-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva®-induced currents demonstrated a specific equilibrium potential similar to glycine. Conclusions: We found that intrathecal administration of Ultiva1 to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva1-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous administrations.

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