title: 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.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan; Department of Pharmacology, Faculty of Medicine, Kinki University, Osaka-Sayama, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kobori
authors.forename: Shuhei
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Kei
authors.initials: K
authors.lastname: Miyagi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004361:Drug Tolerance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects*; D011930:Reaction Time; D013997:Time Factors; D015854:Up-Regulation; D000099149:Ezrin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009020:Morphine; D000099149:Ezrin; C071058:moesin; C071776:radixin