(383) Loss of Gnb5 in Sensory Neurons Leads to Decreased Nociceptive but not Pruriceptive Stimuli in Mice

Abstract

Pain and itch are two somatosensory modalities whose pathologic manifestations cause immense suffering and health burden to millions of people worldwide. Mu-opioid ligands and analogs have been the mainstream therapy against pain, but due to their significant side effects there is an urgent need to have a deeper understanding of the signaling of opioid receptors and to identify newer drug targets which could help improve treatment for these pathologies. Gβ5 is a divergent member of the Gβ subunits of heterotrimeric G proteins which are unique in binding the Gγ like domain present in the R7- RGS proteins. This protein complex acts as a GTPase accelerating protein which terminates Gαi/o signaling, thereby tightly controlling the signaling. Sensory neurons express several Gi/o coupled receptors which have been targeted for analgesia in pathologic pain. Using in situ hybridization and immunoblotting, we document the presence of Gβ5 protein in sensory neurons. Since the Gβ5 protein complex act as a GAP for Gi/o coupled GPCRs, its loss-of-function would be predicted to increase inhibitory signaling in sensory neurons leading a decreased pain or itch sensation. Using sensory neuron specific Advillin Cre mice we knocked down the expression of Gnb5 in sensory ganglia in floxed Gnb5 mice. The Adv Cre-Gnb5 fl/fl mice had a decreased nociceptive sensation for different pain modalities but not itch. Specific nociceptive changes could be blocked by the opioid antagonist, naltrexone or the GABAB antagonist, Saclofen indicating that Gβ5 protein complex could be modulating different Gi/o coupled receptors involved in perceiving different modalities of pain perception. Further analysis of nociceptive stimuli in RGS7 Cre-Gnb5 fl/fl and RGS9 Cre-Gnb5 fl/fl mice revealed significant selective responses to different modalities indicating the role of different R7-RGS partners in pain signaling.