title: Direct Effect of Remifentanil and Glycine Contained in Ultiva® on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses.
abstract: 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 Ultiva® 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 Ultiva® to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva®-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva® between intrathecal and intravenous administrations.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sumie
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiokawa
authors.affiliation: Department of Anesthesiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaura
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Karashima
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hoka
authors.affiliation: Division of Health Sciences, Graduate School of Health Sciences, Kumamoto Health Science University, Kumamoto, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D005998:Glycine / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D000077208:Remifentanil; D013376:Substantia Gelatinosa / Q000166:cytology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D000077208:Remifentanil; D005998:Glycine