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Remifentanil suppresses increase in interleukin-6 mRNA in the brain by inhibiting cyclic AMP synthesis

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Abstract

Purpose

Neuronal inflammation is caused by systemic inflammation and induces cognitive dysfunction. IL-6 plays a crucial role in therapies for neuronal inflammation and cognitive dysfunction. Remifentanil, an ultra-short-acting opioid, controls inflammatory reactions in the periphery, but not in the brain. Therefore, the anti-inflammatory effects of remifentanil in neuronal tissue and the involvement of cAMP in these effects were investigated in the present study.

Methods

Mice were divided into 4 groups: control, remifentanil, LPS, and LPS + remifentanil. Brain levels of pro-inflammatory cytokine mRNA, and serum levels of corticosterone, catecholamine and IL-6 were measured in the 4 groups. The co-localization of IL-6 and astrocytes in the mouse brain after the LPS injection was validated by immunostaining. LPS and/or remifentanil-induced changes in intracellular cAMP levels in cultured glial cells were measured, and the effects of cAMP on LPS-induced IL-6 mRNA expression levels were evaluated.

Results

Remifentanil suppressed increase in IL-6 mRNA levels in the mouse brain, and also inhibited the responses of plasma IL-6, corticosterone, and noradrenaline in an inflammatory state. In the hypothalamus, IL-6 was localized in the median eminence, at which GFAP immunoreactivity was specifically detected. In cultured cells, remifentanil suppressed increase in IL-6 mRNA levels and intracellular cAMP levels after the administration of LPS, and this enhanced IL-6 mRNA expression in response to LPS.

Conclusion

Remifentanil suppressed increase in IL-6 mRNA levels in the brain in an inflammatory state, and this effect may be attributed to its direct action on neuronal cells through the inhibition of intracellular cAMP rather than corticosterone.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers 25463135 and 16K1175008.

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Authors and Affiliations

  1. Department of Dental Anesthesiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan

    Shigeru Maeda & Hitoshi Higuchi

  2. Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Tsugunobu Andoh

  3. Department of Dental Anesthesiology, and Special Care Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Rieko Onishi, Yumiko Tomoyasu & Takuya Miyawaki

Authors
  1. Shigeru Maeda
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  2. Tsugunobu Andoh
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  3. Rieko Onishi
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  4. Yumiko Tomoyasu
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  5. Hitoshi Higuchi
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  6. Takuya Miyawaki
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Contributions

SM conducted the in vivo and in vitro studies; SM wrote the manuscript; AT conducted HPLC; RO and YT conducted some of the in vitro analyses; HH developed the models used for the analyses of in vitro data; MT supervised the work and manuscript preparation.

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Correspondence to Shigeru Maeda.

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The authors declare no competing interests.

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Maeda, S., Andoh, T., Onishi, R. et al. Remifentanil suppresses increase in interleukin-6 mRNA in the brain by inhibiting cyclic AMP synthesis. J Anesth 32, 731–739 (2018). https://doi.org/10.1007/s00540-018-2548-y

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  • DOI: https://doi.org/10.1007/s00540-018-2548-y

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