The goal of the present study was to determine whether the κ-opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic κ-ORA (±)-trans U50,488, its enantiomers (−)-trans(1S,2S)-U50,488 and non κ-ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer (−)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 > U50,488 ≫ (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6–10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the κ-ORAs dynorphin (1–13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor–mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein–mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions.