RGS4 Maintains Chronic Pain Symptoms in Rodent Models

Abstract

Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor 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 female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the 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 hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei 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 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.

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

“…Nonetheless, whatever the mechanism involved in chronic pain and the drugs used for its management, these studies do suggest it is worth further investigating inhibitors of RGS4 as standalone treatments for chronic pain. The fact that two independently generated RGS4 knockout mouse lines, with distinct genetic backgrounds, show no overt behavioral abnormalities (Grillet et al, 2003;Han et al, 2010;Avrampou et al, 2019) provides support for RGS4 as a therapeutic target for pain management.…”

“…Injection of formalin into the mouse hind paw produces a biphasic hyperalgesia consisting of an early phase and a late phase. Mice lacking RGS4 are less hyperalgesic during the late phase (Yoon et al, 2015;Avrampou et al, 2019). Moreover, mice lacking RGS4 recover more quickly from mechanical and cold hypersensitivity following inflammation, caused by Freund's Complete Adjuvant (CFA) injection into the hind paw, or nerve injury and show recovery of wheel running as a measure of pain-depressed behavior (Avrampou et al, 2019).…”

“…Mice lacking RGS4 are less hyperalgesic during the late phase (Yoon et al, 2015;Avrampou et al, 2019). Moreover, mice lacking RGS4 recover more quickly from mechanical and cold hypersensitivity following inflammation, caused by Freund's Complete Adjuvant (CFA) injection into the hind paw, or nerve injury and show recovery of wheel running as a measure of pain-depressed behavior (Avrampou et al, 2019). One potential mechanism to explain both of these observations is the loss of negative regulation by RGS4 of endogenous antinociceptive signaling, possibly involving opioid peptides released in response to the persistent inflammatory pain (Porro et al, 1991;Zangen et al, 1998;Wu et al, 2001).…”

Macrophage regulator of G-protein signaling 12 contributes to inflammatory pain hypersensitivity

“…Recently, several RGS proteins have been shown to regulate pain symptoms. For example, RGS4 maintains chronic pain, and inhibiting RGS4 promotes recovery from sensory hypersensitivity symptoms (14). RGS9 in the spinal cord also contributes to sensory and affective components of pain (15).…”

Synergistic regulation of Rgs4 mRNA by HuR and miR-26/RISC in neurons

“…The negative regulator of G-protein signalling 4 (Rgs4) plays an important role in synaptic plasticity as well as in many diseases of the nervous system, including schizophrenia, addiction, seizure, pain and neurodegenerative disorders [1][2][3][4][5]. Rgs4 encodes a GTPase-activating protein of the G protein-coupled receptor (GPCR) pathway, modulating receptor-mediated neuronal signalling at the synapse [5,6].…”