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

Eizoh Gondoh, Yusuke Hamada, Tomohisa Mori, Yusuke Iwazawa, Asami Shinohara, Michiko Narita, Daisuke Sato, Hiroyuki Tezuka, Takayasu Yamauchi, Mayu Tsujimura, Sara Yoshida, Kenichi Tanaka, Kensuke Yamashita, Haruka Akatori, Kimio Higashiyama, Kazuhiko Arakawa, Yukari Suda, Kanako Miyano, Masako Iseki, Eiichi InadaNaoko Kuzumaki, Minoru Narita

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1565-1574
Number of pages10
JournalBritish Journal of Cancer
Volume127
Issue number8
DOIs
Publication statusPublished - 01-11-2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine'. Together they form a unique fingerprint.

Cite this