Friday, April 11, 2025
4/11/2025
Studies on RGS4-Regulated Pathways in Models of Neuropathic Pain - SUMMARY There is an imminent need for effective medications for the treatment of chronic pain, as most available drugs show low efficacy and tolerability, and in the case of opioids they lead to physic dependence and addiction. This proposal aims to investigate a promising candidate target for pain treatment: the intracellular protein named regulator of G protein signaling 4 (RGS4). RGS4 plays a prominent role in signal transduction by controlling the availability of G protein α and βγ subunits to their effectors and possibly by additional mechanisms. Thus, RGS4 may potently modulate ability of GPCRs to activate their effectors by competing for Gα subunit binding, and may also control the activation of Gβγ targets, including ion channels, kinases and transcription factors. Our earlier work demonstrated that knockout of RGS4 does not affect acute nociceptive responses, or the induction of sensory hypersensitivity in response to peripheral nerve injury (PNI) or inflammation. However, downregulation of RGS4 leads to recovery from sensory hypersensitivity, suggesting that RGS4-controlled pathways are critical for synaptic adaptations that promote the maintenance of chronic pain. Our preliminary data using the spared nerve injury (SNI) and chemotherapy-induced neuropathy (CIPN) models also reveal that long-term PNI in mice regulates the expression of RGS4 in the thalamus and in lumbar dorsal root ganglia (DRG). Here, we will focus on the study of the functional role of RGS4 in the mouse DRG in sensory and affective manifestations of PNI and we will determine neuronal type-specific mechanisms of RGS4 action (with a focus on Mrgprd+ cells in which RGS4 is primarily expressed). We will use mouse genetic tools to determine how interventions in the expression of the RGS4 gene before or after the induction of nerve injury affect sensory, emotional and biochemical manifestations of neuropathic pain states. We will use tissue biochemistry and biosensors in DRG cultures to investigate the role of RGS4 in G protein signaling with emphasis on the competition between RGS4 and the Gα-subunit interacting protein named GINIP (Gai interacting protein). For these studies, we will combine in vitro biosensor assays, with biochemical and behavioral studies with genetically modified mice lacking GINIP globally or in selective nociceptive circuitry. To further investigate the mechanism of RGS4 action under chronic pain, we will use information from recent single nuclei RNA-sequencing (snRNA-Seq) and we will identify and validate cell-type specific gene expression adaptations in lumbar DRGs under prolonger PNI states, with emphasis on cell populations affected by RGS4/GINIP activity. We will continue the analysis and we will test additional genes that are uniquely affected by RGS4 knockout under PNI for their role in the maintenance of sensory hypersensitivity. Understanding the impact of RGS4 and regulated pathways in PNI will help develop novel and efficacious interventions for the management of neuropathic pain.
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