GINIP, a G_αi-Interacting Protein, Functions as a Key Modulator of Peripheral GABA_B Receptor-Mediated Analgesia

Highlights

• GINIP defines two distinct subsets of nonpeptidergic nociceptors

• GINIP is a strong modulator of G_αi-coupled receptors

• GINIP is selectively required for injury-induced mechanical pain

• GINIP null mice are resistant to baclofen-mediated injury-induced analgesia

Summary

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 G_αi-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 GABA_B, 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 GABA_B-receptors signaling.