The proinflammatory cytokine interleukin-1 mediates inflammation and hyperalgesia. However, the underlying mechanisms remain elusive. To better understand such molecular and cellular mechanisms, we investigated how IL-1 modulates the voltage-dependent sodium currents (INa)and its tetrodotoxin resistant (TTX-R) component in capsaicin-sensitive trigeminal nociceptive neurons, both after a brief (5 min) and after a chronic exposure (24 h) of 20ng/ml IL-1. A brief exposure led to a 28% specific (receptor mediated) reduction of INa in these neurons, which were found to be IL-1RI+ on both their soma and nerve endings. In marked contrast, after a 24 h exposure, the total sodium current was specifically increased by 67%, without significantly affecting the TTX-R component. This potentiation of INa was suppressed in the presence of selective inhibitors of PKC and G-protein coupled-signaling pathways, thereby suggesting that INa can be modulated through multiple pathways. In summary, the potentiation of INa through chronic IL-1 signaling in nociceptive sensory neurons may be a critical component of inflammatory-associated hyperalgesia.