Loss of bhlha9 Impairs Thermotaxis and Formalin-Evoked Pain in a Sexually Dimorphic Manner

C-LTMRs are known to convey affective aspects of touch and to modulate injury-induced pain in humans and mice. However, a role for these neurons in temperature sensation has been suggested, but not fully demonstrated. Here, we report that deletion of C-low-threshold mechanoreceptor (C-LTMR)-expressed bhlha9 causes impaired thermotaxis behavior and exacerbated formalin-evoked pain in male, but not female, mice. Positive modulators of GABAA receptors failed to relieve inflammatory formalin pain and failed to decrease the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) selectively in bhlha9 knockout (KO) males. This could be explained by a drastic change in the GABA content of lamina II inner inhibitory interneurons contacting C-LTMR central terminals. Finally, C-LTMR-specific deep RNA sequencing revealed more genes differentially expressed in male than in female bhlha9 KO C-LTMRs. Our data consolidate the role of C-LTMRs in modulation of formalin pain and provide in vivo evidence of their role in the discriminative aspects of temperature sensation. [Display omitted] •BHLHA9 function in C-LTMRs is sexually dimorphic•Loss of BHLHA9 impaired formalin-evoked pain selectively in males•BHLHA9 in C-LTMRs is required for fine discriminative aspects of temperature in males•Loss of BHLHA9 non-cell-autonomously impairs ionotropic GABAergic signaling Bohic et al. demonstrate that mice lacking the transcription factor BHLHA9 exhibit impaired thermotaxis and formalin-evoked pain. BHLHA9 mediates these effects by modulating spinal GABAergic signaling. The data consolidate the role of C-LTRMs in pain sensation and provide in vivo evidence of C-LTRMs in the discriminative aspects of temperature sensation.