We report evidence for a contribution of tetrodotoxin-resistant sodium current (TTX-R I Na) to prostaglandin E 2 (PGE 2)-induced hyperalgesia. Behavioral experiments were performed in rats chronically implanted with spinal cannulae. The study employed intrathecal administration of oligodeoxynucleotide (ODN) antisense to the recently cloned channel underlying TTX-R I Na (PN3/SNS). The nociceptive flexion reflex was employed to determine changes in mechanical stimulus-induced paw-withdrawal threshold. Administration of antisense but not of sense or mismatch ODN, led to a decrease in PGE 2-induced hyperalgesia. PGE 2-induced hyperalgesia returned to normal 7 days after the last injection of antisense ODN. Antisense ODN selectively and significantly reduced TTX-R I Na current density in cultured sensory neurons. Our observations support the hypothesis that modulation of TTX-R I Na, present in peripheral terminals of primary afferent nociceptors, contributes, at least in part, to inflammatory hyperalgesia. Since TTX-R I Na is found only in primary afferent nociceptors, our findings suggest TTX-R I Na as a promising target for novel therapeutic interventions for the treatment of inflammatory pain.