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Involvement of moesin in the development of morphine analgesic tolerance through P-glycoprotein at the blood-brain barrier.

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_name

Drug Metab Pharmacokinet

journal_title

Drug metabolism and pharmacokinetics

authors

Kobori T,Fujiwara S,Miyagi K,Harada S,Nakamoto K,Nakagawa T,Takahashi H,Narita M,Tokuyama S

doi

10.2133/dmpk.DMPK-14-RG-042

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

482-9

issue

6

eissn

1347-4367

issn

1880-0920

pii

DN/JST.JSTAGE/dmpk/DMPK-14-RG-042

journal_volume

29

pub_type

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