BEYOND ION CHANNELS: REVEALING CPT1C AS A NOVEL PLAYER IN NOCICEPTION

Over the past decade, research on pain mechanisms has expanded substantially; however, nociception remains a complex and incompletely understood process. Most studies have focused on the role of ion channels and membrane receptors in sensory neurons and spinal cord (SC) circuits, whereas the contribution of intracellular proteins has received comparatively little attention. Carnitine palmitoyltransferase 1C (CPT1C) is an intracellular protein involved in diverse processes, including learning, memory, and lipid metabolism. Of particular interest is its ability to regulate the trafficking and surface expression of AMPA-type glutamate receptors (AMPARs) through interactions within the endoplasmic reticulum, especially with the GluA1 subunit. In this study, we investigated the contribution of CPT1C to nociceptive processing using CPT1C knockout (KO) mice.
Electrophysiological recordings from small-diameter dorsal root ganglion (DRG) neurons revealed increased excitability in CPT1C-deficient cells without changes in action potential (AP) threshold. Detailed AP analysis showed an enhanced afterhyperpolarization phase in KO nociceptors. In cultured SC neurons, CPT1C deletion resulted in increased intracellular calcium responses to AMPA and glutamate stimulation, accompanied by a modest increase in AMPA-evoked currents. At the molecular level, CPT1C deficiency induced sex-dependent alterations in AMPAR subunit expression. Behaviorally, CPT1C KO mice exhibited heightened sensitivity to mechanical stimuli, an effect that was particularly pronounced in females.
Together, these findings suggest that the increased nociceptive sensitivity observed in CPT1C-deficient animals arises from enhanced peripheral excitability combined with sex-specific changes in spinal AMPAR composition, ultimately modulating synaptic transmission and nociceptive processing.