TY - JOUR
T1 - Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine
AU - Gondoh, Eizoh
AU - Hamada, Yusuke
AU - Mori, Tomohisa
AU - Iwazawa, Yusuke
AU - Shinohara, Asami
AU - Narita, Michiko
AU - Sato, Daisuke
AU - Tezuka, Hiroyuki
AU - Yamauchi, Takayasu
AU - Tsujimura, Mayu
AU - Yoshida, Sara
AU - Tanaka, Kenichi
AU - Yamashita, Kensuke
AU - Akatori, Haruka
AU - Higashiyama, Kimio
AU - Arakawa, Kazuhiko
AU - Suda, Yukari
AU - Miyano, Kanako
AU - Iseki, Masako
AU - Inada, Eiichi
AU - Kuzumaki, Naoko
AU - Narita, Minoru
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.]
AB - 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.]
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U2 - 10.1038/s41416-022-01928-x
DO - 10.1038/s41416-022-01928-x
M3 - Article
C2 - 35945243
AN - SCOPUS:85135811950
SN - 0007-0920
VL - 127
SP - 1565
EP - 1574
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 8
ER -