Endothelin-1 (ET-1) applied to the sciatic nerve or injected into the plantar hindpaw of rats induces pain behavior (ipsilateral hindpaw flinching) and selective excitation of nociceptors by activation of endothelin-A (ET(A)) receptors. To determine the pharmacological profile of the sensory fibers that mediate this pain behavior, we administered lidocaine (LID, a non-selective conduction blocker) or tetrodotoxin (TTX) prior to ET-1. LID (1 or 2%, 0.1 ml) was injected percutaneously into the sciatic notch, or TTX (10 microM, 4 microl) was injected into the sciatic nerve prior to the more distal application of ET-1 (400 microM, 40 microl) onto the sciatic nerve or subcutaneously into the plantar hindpaw (400 microM, 10 microl). LID inhibited ET-1-induced flinching in a dose-dependent manner; the mean total number of flinches was reduced by 39% for 1% LID and by 87% for 2% LID. In contrast, TTX failed to inhibit flinching behavior induced by sciatic nerve application of ET-1 despite a similar magnitude of motor and sensory blockade as that observed with 2% LID. Partial blockade of flinching behavior by intraneural TTX (mean total flinches were reduced by 51%) was observed after subcutaneous injection of ET-1. Unexpectedly, ET-1 prolonged the actions of 1% LID and, even when applied alone, produced clear signs of motor and sensory conduction block. These results are evidence that ET-1-induced pain is transmitted to the central nervous system via sensory fibers using tetrodotoxin-resistant sodium channels, and that ET-1 has analgesic actions that exist despite the activation of local pain pathways.