Quercetin Alleviates Chronic Post-Ischemia Pain in Rats and Inhibits NaV1.7 Sodium Channels

Complex Regional Pain Syndrome type I (CRPS-I) poses a formidable challenge in pain management due to its debilitating symptoms and a lack of effective, targeted therapies. The chronic post-ischemia pain (CPIP) rodent model, which recapitulates the ischemia–reperfusion injury implicated in CRPS-I, provides a robust platform for exploring novel interventions. While quercetin (Que), a natural flavonoid, is recognized for its anti-inflammatory and antioxidant properties, its specific therapeutic efficacy and molecular targets in CRPS-I remain largely unknown. In this study, we evaluated the therapeutic potential of Que in addressing CRPS-related neuropathic pain using the CPIP model. Behavioral assessments revealed that Que significantly attenuates mechanical allodynia and cold hypersensitivity in CPIP rats. To elucidate the underlying mechanism, we investigated Que’s impact on peripheral nociceptive signaling. Whole-cell patch-clamp recordings demonstrated that Que markedly suppresses tetrodotoxin-sensitive (TTX-S) sodium currents in isolated dorsal root ganglion (DRG) neurons. To pinpoint the exact molecular target, we further evaluated Que in a heterologous expression system, confirming that it selectively inhibits Nav1.7 channel currents in transfected HEK293 cells. In addition to its known anti-inflammatory profile, our in vitro findings reveal that Que selectively modulates the Nav1.7 channel, providing new insights into its pleiotropic pharmacological characteristics. By bridging macroscopic analgesic phenotypes with a microscopic channel-blocking mechanism, this study establishes Que as a promising, safe, non-opioid candidate for CRPS-I translational therapy.