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.

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

“…Mice were anesthetized with avertine (250 mg/kg), and the left limb was placed in a lateral position and immobilized. Using the knee as a landmark, an ∼1-cm incision was made in the longitudinal direction (34). The skin was cut, muscles were bluntly dissected, and the sciatic nerve was exposed distal to its trifurcation.…”

Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain

“…The stability of RGS9 is modulated post-translationally via its association with R7BP; binding to R7BP increases its expression, and dissociation makes it susceptible to degradation by cellular cysteine proteases decreasing the expression levels (8). Accordingly, the current model suggests that stimuli that affect RGS9 expression at the post-translational level do so by modulating the extent of its association with R7BP (66,69). Interestingly, in the case of RGS7, the primary role in regulating post-translational stability and expression levels belongs to GPR158 instead of R7BP.…”

RGS9-2 modulates sensory and mood related symptoms of neuropathic pain

“…We next used western blot analysis to determine if neuropathic pain modulates Rgs9-2 expression in the spinal cord and the NAc. Our earlier western blot analysis studies demonstrated Rgs9-2 immunoreactivity levels that were very abundant in the striatum with low to moderate abundances in spinal cord (Terzi, Cao, Agrimaki, Martemyanov and Zachariou 2012). This pattern of expression was also observed using in situ hybridization analysis (Zachariou et al 2003).…”