The Gα-interacting protein RGS4 in dorsal root ganglia maintains molecular and behavioral maladaptations in murine pain models.

Regulator of G protein signaling 4 (RGS4) is a Gα subunit-interacting protein that modulates the functional responses of various G protein-coupled receptors (GPCRs) and that is present in several components of the nociceptive circuitry. Here, we found that RGS4 in lumbar dorsal root ganglia (DRGs) is required for the maintenance of chronic pain states in mice. Rgs4 knockout in Mrgprd+ nonpeptidergic C-fibers was sufficient to attenuate sensory hypersensitivity in several acute and chronic injury models without affecting acute nociceptive responses. Single-nucleus RNA sequencing in ipsilateral lumbar DRGs from mice with prolonged peripheral nerve injury identified cell subset-specific gene expression changes in Rgs4 knockout mice after recovery from mechanical hypersensitivity, including Gabbr2, which encodes the GABAB receptor, in Mrgprd+ fibers. RGS4 competed with Gαi-interacting protein (GINIP) to modulate GABAB receptor signaling, which suppresses neuronal excitability. Analysis of genetically modified mice suggested that imbalances in the interplay between RGS4 and GINIP contribute to the maintenance of sensory hypersensitivity and chronic pain states. Overall, our study reveals critical G protein-modulatory pathways in the DRG that promote the maintenance of sensory hypersensitivity in chronic pain models.