Role of Tachykinins in the Gastrointestinal Tract

The preprotachykinin-A gene-derived peptides substance (SP) and neurokinin A (NKA) are expressed in distinct neural pathways of the mammalian gut. When released from intrinsic enteric or extrinsic primary afferent neurons, they have the potential to influence most digestive effector systems by interaction with tachykinin NK1, NK2 and NK3 receptors. Within the enteric nervous system, SP and NKA mediate slow synaptic transmission and modulate neuronal excitability via stimulation of NK3 and NK1 receptors. As NK1 and NK2 receptors are expressed on muscle and epithelial cells, tachykinins can also directly stimulate gastrointestinal motor activity and facilitate the secretion of fluid and electrolytes. In addition, SP and NKA utilized by extrinsic afferent neurons participate in inflammatory and nociceptive processes. Various gastrointestinal disorders are associated with distinct changes in the expression of tachykinins and their receptors, and there is increasing experimental evidence that tachykinins participate in the dysmotility, hypersecretion, vascular and immunological disturbances associated with infection and inflammation. While tachykinin receptor antagonists are little active in the normal gut, they are able to correct disturbed motility and secretion and to inhibit inflammation and hyperalgesia. Extrapolation of these experimental findings to disorders of the human digestive system identifies tachykinin receptors as novel targets for gastroenterological therapy.