Phosphorylation of the GluN1 subunit in dorsal horn neurons by remifentanil: a mechanism for opioid-induced hyperalgesia

C, Zhang; Li, S S; Zhao, Nan; Yu, Chun Shu

doi:10.4238/2015.march.13.13

Cited by 13 publications

(9 citation statements)

References 29 publications

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“…Studies by others also showed that remifentanil induced increasing of NMDARs expression in spinal cord. 30 – 32 This was verified in our preliminary experiment that remifentanil 1 µg ċ kg −1 ċ min −1 over 60 min infusion induced increasing of p-NR1 and p-NR2B in spinal cord of rats (data not showed). We decided to investigate the effects of chelerythrine, KN93, and PD98059 on remifentanil-induced phosphorylation of NR1 and NR2B subunits in DH neurons.…”

Section: Methodssupporting

confidence: 55%

Enhancement of spinal dorsal horn neuron N-methyl-D-aspartate receptor phosphorylation as the mechanism of remifentanil-induced hyperalgesia: Roles of protein kinase C and calcium/calmodulin-dependent protein kinase II

Zeng

Wan

et al. 2017

Mol Pain

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BackgroundModulation of N-methyl-D-aspartate receptor subunits NR1 and NR2 through phosphorylation mediates opioid-induced hyperalgesia, and activations of protein kinase C and extracellular signal-regulated kinase 1/2 potentiate while activation of calcium/calmodulin-dependent protein kinase II inhibits opioid-induced hyperalgesia. However, the mechanism of opioid-induced hyperalgesia development and in particular the potential interplay between N-methyl-D-aspartate receptors and protein kinase C or calcium/calmodulin-dependent protein kinase II or extracellular signal-regulated kinase 1/2 in the development of remifentanil-induced hyperalgesia is unclear.MethodsRemifentanil (1 µg ċ kg−1 ċ min−1) was given intravenously over 60 min in rats, followed by the infusion of either vehicle solution or the respective inhibitors of protein kinase C (chelerythrine), extracellular signal-regulated kinase II (KN93), or extracellular signal-regulated kinase 1/2 (PD98059). Thereafter, the pain behaviors were evaluated by the paw withdrawal mechanical threshold and paw withdrawal thermal latency. In in vitro studies, fetal spinal cord dorsal horn neurons were primary cultured in the presence of 4 nM remifentanil for 60 min, and then the remifentanil was washed out and replaced immediately by culturing in the absence or presence of chelerythrine, KN93 or PD98059, respectively for up to 8 h. The expressions of N-methyl-D-aspartate receptors subunits and their phosphorylation (NR1, NR2B, p-NR1, p-NR2B) were analyzed by Western blotting after the completion of treatments. Functional changes of N-methyl-D-aspartate receptors were evaluated by electrophysiologic recordings of N-methyl-D-aspartate currents.ResultsRemifentanil induced significant thermal and mechanical hyperalgesia, which were significantly attenuated by Chelerythrine or KN93 but not PD98059. The expressions of NR1, NR2B, p-NR1, and p-NR2B were increased significantly and progressively over time after remifentanil administration, and these increases were all significantly attenuated by either chelerythrine or KN93 but not PD98059. Intriguingly, N-methyl-D-aspartate receptor functional enhancement induced by remifentanil was attenuated by Chelerythrine, KN93, and PD98059.ConclusionsIt is concluded that the enhancements in function and quantity of N-methyl-D-aspartate receptor via phosphorylation of its subunits through protein kinase C and calcium/calmodulin-dependent protein kinase II activation may represent the major mechanism whereby remifentanil induced hyperalgesia.

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Section: Methodssupporting

confidence: 55%

Enhancement of spinal dorsal horn neuron N-methyl-D-aspartate receptor phosphorylation as the mechanism of remifentanil-induced hyperalgesia: Roles of protein kinase C and calcium/calmodulin-dependent protein kinase II

Zeng

Wan

et al. 2017

Mol Pain

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“…Data are mean and SD. *Mean difference (95% CI) 20 (5-35) mm Hg, P¼0.008 and 19 (5-34) mm Hg, P¼0.010 compared with the high-remifentanil with and without naloxone groups, respectively, by unpaired t-test; † 14 (5-24) mm Hg, P¼0.005 and 17(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) mm Hg, P<0.001; ‡ 10 (1-20) beats min À1 , P¼0.043 and 15 (5-25) beats min À1 , P¼0.003; § 14 (5-24) beats min À1 , P¼0.001 and 14 (4-26) beats min À1 , P¼0.002.…”

mentioning

confidence: 99%

Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial

Koo

Yoon

Kim

et al. 2017

British Journal of Anaesthesia

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“…Experimental evidence has investigated the effects of remifentanil, along with ketamine (NMDAR antagonist) and naloxone (μ-opioid receptor antagonist), on GluN1 mRNA levels and the amount of phosphorylated GluN1 in primary cultures of embryonic rat dorsal horn neurons (DHNs) (12). DHNs were isolated from 18-19-day rat embryos and treated with remifentanil or vehicle for 1 h. GluN1 mRNA and protein levels, determined by real time reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively, were significantly and persistently increased by remifentanil exposure compared with the control group (P < 0.05).…”

Section: Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis?mentioning

confidence: 99%

“…These results may partially account for the mechanism of remifentanil-induced hyperalgesia. This increase was prevented by ketamine (NMDAR antagonist) and naloxone (μ-opioid receptors antagonist), thus providing a potential therapeutic mechanism for the prevention of opioid-induced hyperalgesia (12).…”

Section: Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis?mentioning

confidence: 99%

Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis

Candido

2017

PMCR

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Phosphorylation of the GluN1 subunit in dorsal horn neurons by remifentanil: a mechanism for opioid-induced hyperalgesia

Cited by 13 publications

References 29 publications

Enhancement of spinal dorsal horn neuron N-methyl-D-aspartate receptor phosphorylation as the mechanism of remifentanil-induced hyperalgesia: Roles of protein kinase C and calcium/calmodulin-dependent protein kinase II

Enhancement of spinal dorsal horn neuron N-methyl-D-aspartate receptor phosphorylation as the mechanism of remifentanil-induced hyperalgesia: Roles of protein kinase C and calcium/calmodulin-dependent protein kinase II

Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial

Opioid-induced Hyperalgesia: Myth or Burgeoning Public Health Crisis

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