RGS4 maintains chronic pain symptoms in rodent models
- Kleopatra Avrampou*,**,
- Kerri D. Pryce*,
- Aarthi Ramakrishnan*,
- Farhana Sakloth*,
- Sevasti Gaspari*,
- Randal A. Serafini*,
- Vasiliki Mitsi*,
- Claire Polizu*,
- Cole Swartz*,
- Barbara Ligas*,
- Abigail Richards*,
- Li Shen*,
- Fiona B. Carr*, and
- Venetia Zachariou*,^
- *Nash Family Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY
- **University of Crete Faculty of Medicine, Heraklion, Crete, Greece
- ^Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY
- Corresponding author: Venetia Zachariou, Nash Family Department of Neuroscience, Friedman Brain Institute and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York NY, tel. 212-6598612, e-mail: venetia.zachariou{at}mssm.edu
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Author contributions: K.A., K.D.P., A.R., F.S., S.G., R.A.S., V.M., L.S., F.C., and V.Z. designed research; K.A., K.D.P., A.R., F.S., R.A.S., V.M., C.P., C.S., B.L., A.K.R., F.C., and V.Z. performed research; K.A., K.D.P., A.R., F.S., S.G., R.A.S., V.M., C.P., C.S., B.L., A.K.R., L.S., F.C., and V.Z. analyzed data; K.A., K.D.P., A.R., F.S., S.G., R.A.S., V.M., C.P., L.S., F.C., and V.Z. edited the paper; V.Z. wrote the paper.
Abstract
Regulator of G protein signaling 4 (RGS4) is a potent modulator of G protein-coupled receptor (GPCR) signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and in female mice. Using paradigms of peripheral inflammation and nerve injury, we show that prevention of RGS4 action leads to recovery from mechanical and cold hypersensitivity and increases motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's adjuvant (CFA) model of hind paw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei (VPL-THL) promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity Pathway Analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, western blot analysis shows increased expression of metabotropic glutamate receptor 2 (mGluR2) in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.
SIGNIFICANCE STATEMENT
There is an imminent need for safe and efficient chronic pain medications. RGS4 is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hind paw inflammation or hind limb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
Footnotes
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The authors declare no competing financial interests.
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This study was supported by National Institute of Neurological Disorders and Stroke NS086444 (V.Z.), NS093537 (V.Z.), and National Institute on Drug Abuse PPG-POIDAO8227 (V.Z.), T32 5T32DA007135-34 (KP). C.P. is a recipient of the Irene and Eric Simon Brain Research Foundation Summer Fellowship (2016).
- Received December 16, 2018.
- Revision received May 2, 2019.
- Accepted June 27, 2019.
- Copyright © 2019 the authors
