The effects of various sodium channel blocking agents on acute thermal and mechanical nociception, as assessed using the plantar and tail pressure tests, respectively, were compared with the effects of morphine. The drugs used were mexiletine, lidocaine, carbamazepine, phenytoin, eperisone, tolperisone, and zonisamide. The sodium channel blocking agents exhibited a rather preferential elevation of the threshold for thermal nociception. By contrast, morphine produced similar analgesic effects on thermal and mechanical nociception. In the sciatic nerve isolated from mice, mexiletine, lidocaine, eperisone, and tolperisone impaired the propagation of low frequency action potentials (evoked at 0.2 Hz). Carbamazepine, phenytoin, and zonisamide generated a more frequency-dependent local anesthetic action with their obvious effects on higher frequency action potentials (evoked at 5 and/or 10 Hz). Our results show that sodium channel blocking agents have a preferential antinociceptive action against thermal stimulation that is likely to be attributed to their local anesthetic action.