Previously, we showed that nerve-mast cell cross-talk can occur bidirectionally and that substance P is a mediator to activate mast cells. Here, we have studied the mediators to activate nerves cocultured with mast cells. Addition of antigen to the cocultures of superior cervical ganglia (SCG) and rat basophilic leukemia cells (RBLs) elicited Ca(2+) response in RBLs and after a lag period induced Ca(2+) signal in SCG neurites. Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (purinergic receptor antagonist) or apyrase (ATP-hydrolyzing enzyme) reduced the Ca(2+) signals in neurites, indicating that ATP released from activated mast cells was one of important mediators to activate nerves.