Direct Effect of Remifentanil and Glycine Contained in Ultiva (R) on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses

作者：Sumie Makoto; Shiokawa Hiroaki^*; Yamaura Ken; Karashima Yuji; Hoka Sumio; Yoshimura Megumu

来源：PLos One, 2016, 11(1): e0147339.

DOI：10.1371/journal.pone.0147339

Background
Ultiva (R) is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short-acting mu-opioid receptor agonist. Ultiva (R) is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva (R) provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva (R) contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva (R) potentially complicates its effects. We examined how Ultiva (R) 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 (R) 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 (R) 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 (R). Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva (R)-induced outward currents and suppression of mEPSCs were not inhibited by the mu-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva (R)-induced currents demonstrated a specific equilibrium potential similar to glycine.
Conclusions
We found that intrathecal administration of Ultiva (R) to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva (R)-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva (R) between intrathecal and intravenous administrations.

• 出版日期2016-1-15