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Involvement of Spinal PKMζ Expression and Phosphorylation in Remifentanil-Induced Long-Term Hyperalgesia in Rats

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Abstract

Up-regulation of GluN2B-containing N-methyl-d-aspartate receptors (NMDARs) expression and trafficking is the key mechanism for remifentanil-induced hyperalgesia (RIH), nevertheless, the signaling pathway and pivotal proteins involved in RIH remain equivocal. PKMζ, an isoform of protein kinase C (PKC), maintains pain memory storage in neuropathic pain and inflammatory pain, which plays a parallel role regulated by NMDARs in long-term memory trace. In the present study, Zeta Inhibitory Peptide (ZIP), a PKMζ inhibitor, and a selective GluN2B antagonist Ro-256981 are injected intrathecally before remifentanil infusion (1 μg kg−1 min−1 for 1 h, iv) in order to detect whether GluN2B contributes to RIH through affecting synthesis and activity of PKMζ in spinal dorsal horn. Nociceptive tests are measured by Paw withdrawal mechanical threshold (PWT) and paw withdrawal thermal latency (PWL). The L4–L6 segments of dorsal horn taken from rats with RIH are for determining expression of PKMζ and pPKMζ by Western blot and immunohistochemistry. Our data suggest that remifentanil infusion causes an increase of PKMζ in expression and phosphorylation in rats with nociceptive sensitization, beginning at 2 h, peaked at 2 days, and returned to basal level at 7 days. ZIP (10 ng) could block behavioral sensitization induced by remifentanil. Ro25-6981 dosage-dependently attenuated mechanical and thermal hyperalgesia and reversed expression of PKMζ and pPKMζ, indicating that GluN2B-containing NMDA receptor facilitates development of RIH through mediating expression and activity of spinal PKMζ in rats. Although detailed mechanisms require further comprehensive study, the preventive role of Ro25-6981 and ZIP provide novel options for the effective precaution of RIH in clinics.

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Abbreviations

NMDARs:

N-methyl-d-aspartate receptors

RIH:

Remifentanil-induced hyperalgesia

PKC:

Protein kinase C

ZIP:

Zeta inhibitory peptide

PWT:

Paw withdrawal mechanical threshold

PWL:

Paw withdrawal thermal latency

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Acknowledgments

This work was supported by research grants from the National Natural Science Foundation of China (81571077, 81371245, 81301025, and 81400908) and Science and Technology Supported Key Project of Tianjin (12ZCZDSY03000).

Author contribution

Qi Zhao helped design the study, conduct the study, analyze the data, and write the manuscript. Linlin Zhang helped design the study, conduct the study, and analyze the data. Ruichen Shu helped conduct the study and analyze the data. Chunyan Wang and Haiyun Wang helped design the study and analyze the data. Yonghao Yu helped conduct the study. Guolin Wang helped design the study, analyze the data, and write the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Qi Zhao, Linlin Zhang, Ruichen Shu, Chunyan Wang, Yonghao Yu, Haiyun Wang & Guolin Wang

  2. Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China

    Qi Zhao, Linlin Zhang, Ruichen Shu, Chunyan Wang, Yonghao Yu, Haiyun Wang & Guolin Wang

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  1. Qi Zhao
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  2. Linlin Zhang
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Correspondence to Guolin Wang.

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Zhao, Q., Zhang, L., Shu, R. et al. Involvement of Spinal PKMζ Expression and Phosphorylation in Remifentanil-Induced Long-Term Hyperalgesia in Rats. Cell Mol Neurobiol 37, 643–653 (2017). https://doi.org/10.1007/s10571-016-0401-0

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