SUBSTANCE-P ACTIVATION OF ENTERIC NEURONS IN RESPONSE TO INTRALUMINALCLOSTRIDIUM-DIFFICILE TOXIN-A IN THE RAT ILEUM

Background & Aims: Nerves have been suggested to mediate the effects o f bacterial toxins in intestinal diseases. However, the mechanisms inv olved are unknown. This study examined endogenous substance P (SP) act ivation of the substance P receptor (SPR) on enteric neurons in the ra t ileum after exposure to intraluminal Clostridium difficile toxin A. Methods: After intraluminal injection of toxin A in ileal loops, tissu e was examined for pathological changes by histology and for SPR activ ation by immunocytochemical analysis of SP-induced SPR endocytosis. Re sults: After toxin A administration, >70% of enteric neurons showed SP R endocytosis and became swollen with thickened dendrites. In contrast , SPRs in control rats were largely confined to the plasma membrane. R ats denervated of primary afferent fibers with neonatal capsaicin inje ction and animals pretreated with a nonpeptide SPR antagonist showed f ew endosomal SPRs, and the pathological inflammatory effects of toxin A were ablated. Conclusions: Intraluminal toxin A causes the release o f SP from primary afferent neurons; this endogenous SP then acts on en teric neurons in the submucosal and myenteric plexuses. SP is the prim ary mediator of an axon reflex mediating neurogenic inflammation in th e intestine. SPR blockade may prove to be a novel therapy used to prev ent intestinal inflammation.