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Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance.

Abstract：

BACKGROUND:Intraoperative remifentanil infusions have been associated with postoperative opioid-induced hyperalgesia and tolerance. Using a previously identified subpopulation of spinal neurons that displays an augmentation in N-methyl-D-aspartate (NMDA) receptor current after chronic morphine, investigations were undertaken to determine whether remifentanil induces acute increases in NMDA responses that are concentration dependent and receptor subtype dependent. METHODS:Electrophysiologic recordings of NMDA current were made from cultured rat dorsal horn neurons treated with remifentanil at various concentrations for 60 min. Selective mu- or delta-opioid receptor inhibitors and agonists were used to determine the site of action of remifentanil. RESULTS:Remifentanil at 4, 6, and 8 nM, but not higher or lower concentrations, caused significant mean increases in NMDA peak current amplitude of 37.30% (P < 0.001), 30.19% (P < 0.001), and 23.52% (P = 0.025), respectively, over control conditions. This occurred by 36 min of remifentanil perfusion and persisted throughout its washout. Inhibition by 100 nM naloxone or 1 nM naltrindole attenuated the remifentanil-induced NMDA response increase. Selective delta-opioid agonists [D-Pen(2), D-Pen(5)]enkephalin and deltorphin II displayed a similar bell-shaped concentration-response relation for the enhancement of NMDA responses, and 10 nM deltorphin II occluded the effects of 4 nM remifentanil on NMDA responses. CONCLUSIONS:Clinically relevant concentrations of remifentanil induce rapid, persistent increases in NMDA responses that mirror the development of remifentanil-induced hyperalgesia and tolerance. NMDA enhancement by remifentanil is dependent on the activation of both mu- and delta-opioid receptors and is inducible solely by delta-opioid receptor activation. Therefore, selective delta-opioid inhibition may attenuate acute paradoxical increases in pain and tolerance to opioids.

journal_name

Anesthesiology

journal_title

Anesthesiology

authors

Zhao M,Joo DT

doi

10.1097/ALN.0b013e31817f4c5d

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

308-17

issue

eissn

0003-3022

issn

1528-1175

pii

00000542-200808000-00020

journal_volume

109

pub_type

杂志文章

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Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance.