Gut microbiota-derived short-chain fatty acid suppresses the excitability of rat nociceptive secondary neurons via G-protein-coupled receptor 41 signaling.

Short-chain free fatty acids (SCFAs) are generated by gut microbiota through anaerobic fermentation of dietary fibers. Although gut microbiota-derived SCFAs modulate voltage-gated Ca²⁺ channels via G-protein-coupled receptor 41 (GPR41) in isolated sympathetic ganglion neurons, the influence of SCFAs, specifically propionic acid (PA), on the excitability of nociceptive neurons under in vivo conditions has yet to be ascertained. In the current study we assessed whether systemic PA administration diminishes the excitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) wide-dynamic range neurons responding to mechanical stimulation. Extracellular single-unit recordings from SpVc wide-dynamic range neurons were performed in anesthetized rats after mechanical stimulation of the orofacial region. PA significantly and reversibly inhibited the mean firing frequency of SpVc neurons in response to both non-noxious and noxious mechanical stimuli in a dose-dependent manner. Simultaneous administration of a GPR41 inhibitor abolished the PA-induced inhibited firing rate of SpVc neurons, indicating that systemic PA decreased the excitability of nociceptive secondary trigeminal neurons by activating GPR41 signaling-mediated inhibition of voltage-gated Ca²⁺ channels in the central terminals of the SpVc. Modulation of trigeminal nociception by systemic SCFA administration indicates that gut microbiota-derived SCFAs could be effective analgesic agents for relieving trigeminal pain, creating a new therapeutic strategy for the management of trigeminal pain, including clinical pain.