The T-type calcium channel Cav3.2 emerges as a key regulator of sensory functions, but its expression pattern within primary afferent neurons and its contribution to modality-specific signaling remain obscure. Here, we elucidate this issue using a unique knockin/flox mouse strain wherein Cav3.2 is replaced by a functional Cav3.2-surface-ecliptic GFP fusion. We demonstrate that Cav3.2 is a selective marker of two major low-threshold mechanoreceptors (LTMRs), Aδ- and C-LTMRs, innervating the most abundant skin hair follicles. The presence of Cav3.2 along LTMR-fiber trajectories is consistent with critical roles at multiple sites, setting their strong excitability. Strikingly, the C-LTMR-specific knockout uncovers that Cav3.2 regulates light-touch perception and noxious mechanical cold and chemical sensations and is essential to build up that debilitates allodynic symptoms of neuropathic pain, a mechanism thought to be entirely A-LTMR specific. Collectively, our findings support a fundamental role for Cav3.2 in touch/pain pathophysiology, validating their critic pharmacological relevance to relieve mechanical and cold allodynia.

C-low-threshold mechanoreceptors (C-LTMRs) are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs. Genetic labeling in combination with electrophysiological recordings show that TAFA4+ neurons have intrinsic properties of mechano-nociceptors. TAFA4-null mice exhibit enhanced mechanical and chemical hypersensitivity following inflammation and nerve injury as well as increased excitability of spinal cord lamina IIi neurons, which could be reversed by intrathecal or bath application of recombinant TAFA4 protein. In wild-type C57/Bl6 mice, intrathecal administration of TAFA4 strongly reversed carrageenan-induced mechanical hypersensitivity, suggesting a potent analgesic role of TAFA4 in pain relief. Our data provide insights into how C-LTMR-derived TAFA4 modulates neuronal excitability and controls the threshold of somatic sensation.

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.