Noxious stimuli are of different modalities, including thermal (heat and cold), mechanical and chemical stimuli. Nociception is a type of sensation triggered by noxious stimuli and serves as an important protection to the body. The mechanisms underlying nociceptive modalities remain to be fully explored.

Transduction of nociceptive signals requires a cascade of molecules with distinct sensory functions. However, accumulated evidence suggests that the discovered thermosensors are partially involved in heat nociception, opening the door for additional players. The present study reveals that FGF13 is critical to the transmission of noxious heat signaling, and that the FGF13 and Na_v1.7 interaction during noxious heat stimulation functions as a novel mechanism for heat nociception.

Using the single-cell transcriptome analysis and in vivo electrophysiological recording, ZHANG’s Lab recently has identified 10 types of the dorsal root ganglion (DRG) neurons in adult mice, including six types of mechanoheat nociceptors. FGF13 is selectively expressed in the mechanoheat nociceptive neurons.

A series of behavioral paradigms were used to assess the nociception of FGF13 conditional knockout mice, with the FGF13 gene specifically deleted in nociceptive neurons. Mice lacking FGF13 in the DRG neurons selectively lost heat nociception, while other sensations were largely unaltered. The fMRI data showed that several brain regions almost lost the signals responding to peripheral noxious heat stimulation.

Furthermore, FGF13 interacted with a voltage-gated sodium channel Na_v1.7, and increased the Na_v1.7 current. During the noxious heat stimulation, the FGF13/Na_v1.7 interaction was increased to maintain the Na_v1.7 level in the plasma membrane and therefore sustain the action potential firing, enabling the transmission of nociceptive heat signaling to the central nervous system. The C-terminus of Na_v1.7 served as the region mediating the FGF13/Na_v1.7 interaction. The effect of interrupting FGF13/Na_v1.7 interaction mimicked the phenotype of FGF13 knockout mice. Thus, FGF13 regulates heat nociception by interacting with Na_v1.7.

In this study, ZHANG’s Lab discovered that FGF13 expressed in the mechanoheat nociceptors specifically regulate heat nociception. Also, they unveiled that the FGF13/Na_v1.7 interaction is a critical mechanism for heat nociception. These findings provide a new conceptual advance in pain mechanism and a novel pain therapeutic target.