GINIP, a G αi -Interacting Protein, Functions as a Key Modulator of Peripheral GABA B Receptor-Mediated Analgesia

Abstract

One feature of neuropathic pain is a reduced GABAergic inhibitory function. Nociceptors have been suggested to play a key role in this process. However, the mechanisms behind nociceptor-mediated modulation of GABA signaling remain to be elucidated. Here we describe the identification of GINIP, a Gαi-interacting protein expressed in two distinct subsets of nonpeptidergic nociceptors. GINIP null mice develop a selective and prolonged mechanical hypersensitivity in models of inflammation and neuropathy. GINIP null mice show impaired responsiveness to GABAB, but not to delta or mu opioid receptor agonist-mediated analgesia specifically in the spared nerve injury (SNI) model. Consistently, GINIP-deficient dorsal root ganglia neurons had lower baclofen-evoked inhibition of high-voltage-activated calcium channels and a defective presynaptic inhibition of lamina IIi interneurons. These results further support the role of unmyelinated C fibers in injury-induced modulation of spinal GABAergic inhibition and identify GINIP as a key modulator of peripherally evoked GABAB-receptors signaling.

Genetic ablation of GINIP-expressing primary sensory neurons strongly impairs Formalin-evoked pain

“…Here, we show that ablation of GINIP + neurons led to a significant decrease in the first phase and a nearly complete abolition of the second phase of formalin-evoked pain. Given that GINIP is expressed in MRGPRD + neurons and in C-LTMRs and that this protein is totally excluded from TRPV1 + , MRGPRB4 + , Aβ, and Aδ low threshold mechanoreceptors6, our results suggest that C-LTMRs likely represent the subpopulation of neurons that contribute to the modulation of formalin-evoked pain.…”

“…In a recent study6, we generated a versatile mouse model that allows ginip gene global inactivation and an inducible and tissue-specific ablation of GINIP-expressing neurons (Fig. 1A).…”

“…In a previous study, Cavanaugh and colleagues demonstrated that MRGPRD + neurons play a critical role in acute and inflammation-induced mechanical pain1. Given that GINIP + neurons encompass MRGPRD + neurons and C-LTMRs6, we sought to analyze the mechanical sensitivity of GINIP-DTR mice under acute, inflammatory and nerve injury conditions using the Von Frey test. We found no differences in acute mechanical thresholds between GINIP +/+ and GINIP-DTR mice before and after DT injection (Fig.…”

“…GINIP flx/+ mice were previously generated in the laboratory6. Special efforts were made to minimize the number as well as the stress and suffering of mice used in this study.…”

“…study2. We and others have shown that low threshold mechanoreceptors Aβ, Aδ, C-LTMRs and the MRGPRB4 + neurons, express neither MRGPRD nor TRPV1 in mice4567, implying that these populations of neurons are likely involved in sensing and transducing formalin-evoked pain. Here we used our recently engineered ginip versatile mouse model that allows an inducible and tissue specific ablation of GINIP-expressing neurons.…”