title: R7BP modulates opiate analgesia and tolerance but not withdrawal.
abstract: The adaptor protein R7 family binding protein (R7BP) modulates G protein coupled receptor (GPCR) signaling and desensitization by controlling the function of regulator of G protein signaling (RGS) proteins. R7BP is expressed throughout the brain and appears to modulate the membrane localization and stability of three proteins that belong to R7 RGS family: RGS6, RGS7, and RGS9-2. RGS9-2 is a potent negative modulator of opiate and psychostimulant addiction and promotes the development of analgesic tolerance to morphine, whereas the role of RGS6 and RGS7 in addiction remains unknown. Recent studies revealed that functional deletion of R7BP reduces R7 protein activity by preventing their anchoring to the cell membrane and enhances GPCR responsiveness in the basal ganglia. Here, we take advantage of R7BP knockout mice in order to examine the way interventions in R7 proteins function throughout the brain affect opiate actions. Our results suggest that R7BP is a negative modulator of the analgesic and locomotor activating actions of morphine. We also report that R7BP contributes to the development of morphine tolerance. Finally, our data suggest that although prevention of R7BP actions enhances the analgesic responses to morphine, it does not affect the severity of somatic withdrawal signs. Our data suggest that interventions in R7BP actions enhance the analgesic effect of morphine and prevent tolerance, without affecting withdrawal, pointing to R7BP complexes as potential new targets for analgesic drugs.
authors.affiliation: Department of Basic Sciences, University of Crete, Faculty of Medicine, Laboratory of Pharmacology, Heraklion, Crete, Greece.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Terzi
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.forename: Ioanna
authors.initials: I
authors.lastname: Agrimaki
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009021:Morphine Dependence / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; C499440:R7BP protein, mouse; D020710:RGS Proteins
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