The TASK-1 and TASK-3 activator JG-C3-98 attenuates cold and mechanical responses in primary somatosensory neurons

K2P channels underlie background K⁺ currents that act as brakes on neuronal excitability. In the somatosensory system, the K2P channels TASK-1 and TASK-3 play a relevant role in cold sensing, mechanosensitivity, and pain. Combining molecular docking and molecular dynamic simulations, patch-clamp recordings of recombinant channels, Ca²⁺-imaging and patch-clamp analysis in cultured primary somatosensory neurons from trigeminal and dorsal root ganglia, extracellular recording of the nerve endings of trigeminal neurons at the corneal surface, and behavioral analysis in mice models of acute, irritative, and neuropathic pain, we described and characterized the novel and rationally designed activator of TASK-1 and TASK-3 channels JG-C3-98. In HEK293 cells, JG-C3-98 showed a strong activation effect on TASK-1 and TASK-3, but not on TRAAK, TREK-1, TREK-2, and TRESK. In cultured primary somatosensory neurons, we have found that JG-C3-98 shifted the thermal threshold of cold thermoreceptor neurons to lower temperatures and reduced the maximal mechanically evoked responses in neurons responding to hypoosmotic stimulation. In ex vivo recordings of corneal cold-sensitive neurons, JG-C3-98 also shifted the thermal threshold of these nerve endings to lower temperatures. In a group of cultured dorsal root ganglia neurons, electrophysiological analysis suggests that JG-C3-98 reduces excitability and activates an outward current compatible with TASK-1/3 channels. Besides, intraplantar administration of a single dose of JG-C3-98 in the hind paw increases the threshold of the mechanically evoked pain sensitivity and reduces AITC-evoked nociceptive responses in mice. Importantly, in a model of neuropathic pain induced by chronic constriction of the sciatic nerve, we have found that cold allodynia resulting from this form of peripheral nerve damage is also reduced by intraplantar administration of a single dose of JG-C3-98 in the hind paw. Altogether, these results suggest that JG-C3-98 could be a new and potentially effective pharmacological tool for reducing cold and mechanical sensitivity across different somatosensory territories, both in physiological and pathophysiological conditions, and serve as a molecular scaffold for developing novel, more effective antinociceptive compounds that specifically act as TASK channels activators.