Changes in immunoreactive substance P concentrations were investigated in longitudinal muscle-myenteric plexus preparations from the inflamed jejunum of Trichinella spiralis-infected rats. The substance P concentration increased within 2 days of infection and increased fivefold by day 6; in contrast, there was no significant increase in substance P in the noninflamed ileum. In vitro exposure of preparations from infected rats to scorpion venom reduced substance P levels by 88%. In addition, no increase in substance P was observed in rats that had been treated with capsaicin as neonates or as adults before infection. Treatment of infected rats with betamethasone attenuated the inflammatory response to the infection and prevented the increase in substance P. Furthermore, no significant increase in substance P concentration was seen in congenitally athymic rats infected with T. spiralis. This study is consistent with the hypothesis that inflammation increases substance P in myenteric nerves by a process that involves T lymphocytes.