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Translational Therapeutics

Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine

British Journal of Cancer volume 127, pages 1565–1574 (2022)Cite this article

Subjects

Abstract

Background

It has been considered that activation of peripheral μ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine.

Methods

The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and β-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine.

Results

Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in β-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice.

Conclusions

The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.

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Fig. 1: Evaluation of the antagonistic activity of naldemedine for µ-opioid receptors.
Fig. 2: Evaluation of the pharmacological profiles of the peripheral µ-opioid receptor antagonist naldemedine.
Fig. 3: Changes in tumour growth by the repeated treatment with peripheral µ-opioid receptor agonists and antagonists.
Fig. 4: Changes in the number of spleen-derived immune cells by the repeated administration of naldemedine in LLC cell-transplanted mice.
Fig. 5: Changes in mRNA expression of immune checkpoint receptors and cytotoxicity-related genes in CD8+ T cells by the repeated administration of naldemedine in LLC cell-transplanted mice.
Fig. 6: Changes in mRNA expression of opioid receptors and pattern recognition receptors in lymphocytes by the repeated administration of naldemedine in LLC cell-transplanted mice.

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Data availability

All data presented within the article are available upon request from the corresponding author.

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Acknowledgements

The authors thank Ms. Kana Morita, Ms. Arisa Gina, Ms. Anna Hori, Mr. Shoki Matsumura, Mr. Takuya Kurimura, Ms. Natsumi Kawamura and Ms. Mayu Takagi for their help with the experiments.

Funding

This work was supported in part by grants from the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018, S1411019. This research was also supported by Hoshi University.

Author information

Author notes

  1. These authors contributed equally: Eizoh Gondoh, Yusuke Hamada.

Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Eizoh Gondoh, Masako Iseki & Minoru Narita

  2. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Eizoh Gondoh, Yusuke Hamada, Tomohisa Mori, Yusuke Iwazawa, Asami Shinohara, Daisuke Sato, Mayu Tsujimura, Sara Yoshida, Kenichi Tanaka, Kensuke Yamashita, Kazuhiko Arakawa, Yukari Suda, Naoko Kuzumaki & Minoru Narita

  3. Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yusuke Hamada, Michiko Narita, Daisuke Sato, Sara Yoshida, Kenichi Tanaka, Yukari Suda, Kanako Miyano, Naoko Kuzumaki & Minoru Narita

  4. Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan

    Michiko Narita

  5. Department of Cellular Function Analysis, Research Promotion Headquarters, Fujita Health University, Aichi, Japan

    Hiroyuki Tezuka

  6. Institute of Medicinal Chemistry, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Takayasu Yamauchi, Haruka Akatori & Kimio Higashiyama

  7. Department of Anesthesiology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Eiichi Inada

Authors
  1. Eizoh Gondoh
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Contributions

EG, YH, TM and Minoru N wrote the manuscript. NK and Minoru N edited the manuscript. Michiko N, YS, KM and NK conducted in vitro studies. YH, YI, AS, DS, MT, SY, KT and KY conducted in vivo studies. HT provided technical support. HA, TY and KH synthesised naldemedine. EG, KA, MI and EI provided medical comments. NK and Minoru N supervised the overall project. All of the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Naoko Kuzumaki or Minoru Narita.

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The authors declare no competing interests.

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All animal studies were conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals at Hoshi University, as adopted by the Committee on Animal Research of Hoshi University.

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Gondoh, E., Hamada, Y., Mori, T. et al. Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine. Br J Cancer 127, 1565–1574 (2022). https://doi.org/10.1038/s41416-022-01928-x

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