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.

Regulation of breast cancer resistance protein and P-glycoprotein by ezrin, radixin and moesin in lung, intestinal and renal cancer cell lines

“…Although we did not examine how each transporter was regulated, our prior research showed that P‐gp transport activity and membrane localization in mouse small intestine, Caco‐2 and human hepatoblastoma HepG2 cells both require Rdx . However, other researchers have found that not only Rdx, but also Ezr or Msn regulates P‐gp membrane localization in various tissues . Therefore, it seems likely that one or more of the ERM proteins might regulate BCRP and P‐gp localization on the plasma membrane in the cell lines used in this study.…”

“…membrane localization in various tissues. [16,17] Therefore, it seems likely that one or more of the ERM proteins might regulate BCRP and P-gp localization on the plasma membrane in the cell lines used in this study.…”

“…[14] On the other hand, in the liver, Rdx alone controls P-gp, [15] while in brain capillary endothelial cells, ezrin (Ezr) and moesin (Msn) are involved in the membrane expression and transport function of P-gp. [16,17] We and other researchers have shown that P-gp membrane localization and function are regulated by Rdx in the intestine. [8,[18][19][20] Moreover, we established that there are tissue-specific differences in the effects of ERM proteins on P-gp function between intestinal cancer Caco-2 cells and renal cancer Caki-1 cells.…”

“…We previously showed that P‐gp localization and function are also regulated by ERM proteins in the intestine . On the other hand, in the liver, Rdx alone controls P‐gp, while in brain capillary endothelial cells, ezrin (Ezr) and moesin (Msn) are involved in the membrane expression and transport function of P‐gp . We and other researchers have shown that P‐gp membrane localization and function are regulated by Rdx in the intestine .…”

Advances in Studies of P-Glycoprotein and Its Expression Regulators

“…The membrane localization and function of P-gp in the brain capillary endothelial cells are regulated by Msn in morphine-treated mice and/or Ezr in sphingomyelin synthase-deficient mice. 53,54) In summary, it appears that P-gp localization and function could be regulated by different ERM proteins in different normal tissues (Fig. 2, Table 1).…”