Involvement of Moesin in the Development of Morphine Analgesic Tolerance through P-glycoprotein at the Blood–Brain Barrier
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- KOBORI Takuro
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University Department of Pharmacology, Faculty of Medicine, Kinki University
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- FUJIWARA Shuhei
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University
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- MIYAGI Kei
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University
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- HARADA Shinichi
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University
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- NAKAMOTO Kazuo
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University
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- NAKAGAWA Takayuki
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences
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- TAKAHASHI Hideo
- Department of Pharmacology, Faculty of Medicine, Kinki University
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- NARITA Minoru
- Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences
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- TOKUYAMA Shogo
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences
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Abstract
Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by Western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.
Journal
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- Drug Metabolism and Pharmacokinetics
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Drug Metabolism and Pharmacokinetics 29 (6), 482-489, 2014
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