In the lower esophageal sphincter (LES) and body circular muscle (BCM) from opossum, nerves appeared to innervate the interstitial cells of Cajal more closely than they innervated smooth muscle cells, and it was postulated that these cells might mediate nonadrenergic, noncholinergic (NANC) nerve effects. Tissues were treated with a toxin, selective for structures with Na channels, the venom of the scorpion, Leiurus quinquestriatus, to determine its morphological effects on nerves and other structures and its effect on responses of LES and BCM to NANC nerve stimulation by field stimulation with 0.5- and 5-ms pulses. Relaxations to 5-ms pulses are tetrodotoxin-insensitive and might result from the release of mediators from nerve terminals by a different, Na channel independent mechanism or from activation of a nonneural structure with a longer time constant than nerve. Scorpion venom relaxes the LES temporarily and, like tetrodotoxin, abolished responses of LES and BCM to 0.5-ms pulses of field stimulation, but not responses to 5-ms pulses of field stimulation. When responses to 0.5 ms of field stimulation were first inhibited, some nerve varicosities were damaged. Later nearly all were depicted markedly of synaptic vesicles. Venom did not structurally damage other cells. The venom effects to relax LES and to damage nerves were prevented by tetrodotoxin pretreatment, suggesting that venom released an inhibitory mediator and destroyed synaptic vesicles by acting on Na channels. The finding that interstitial cells of Cajal, which often had gap junction contacts to smooth muscle and close associations with nerves, were resistant to scorpion venom while the nerves that innervate them were not, is consistent with the hypothesis that interstitial cells are intercalated between the nerves and muscles and may mediate tetrodotoxin-insensitive responses to field stimulation.