Implications of Tachykinins and Calcitonin Gene-Related Peptide in Inflammatory Bowel Disease

Abstract

Calcitonin gene-related peptide (CGRP) and the preprotachykinin A gene-derived peptides substance P (SP) and neurokinin A (NKA) are expressed in extrinsic primary afferent nerve fibres and intrinsic enteric neurons of the gut. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK₁, NK₂ and NK₃ receptors, while the gastro-intestinal actions of CGRP are brought about by CGRP₁ and possibly other CGRP receptors. These neuropeptide transmitters are expressed by enteric neurons, intestinal muscle, epithelium and vascular system in a cell-specific manner and enable SP, NKA and CGRP to influence motility, electrolyte and fluid secretion, vascular and immune functions in a peptide- and region-specific fashion. Inflammatory disorders of various aetiology involve changes in the peptidergic innervation of the gut, and inflammatory bowel disease is associated with NK₁ receptor upregulation in intestinal blood vessels and lymphoid structures. Some of these alterations are reproduced in experimental models of gastro-intestinal disease, and there is mounting evidence that an imbalanced function of peptidergic neurons contributes to motor, secretory, vascular and immunological disturbances in intestinal anaphylaxis, infection and inflammation. In a therapeutic perspective it seems conceivable that tachykinin and CGRP receptors antagonists can be employed as spasmolytic, antidiarrhoeal, anti-inflammatory and antinociceptive drugs.

Attenuation of acute experimental colitis by preventing NPY Y1 receptor signaling

“…Other mediators implicated in the pathogenesis of colitis are neuropeptides released from enteric and sensory afferent neurons (37). These peptides have been shown to modulate different aspects of mucosal function, including blood flow and secretion, and may play a role in the recruitment of granulocytes and lymphocytes and in the modulation of mast cell activation (14,18).Stimulation and activation of capsaicin-sensitive sensory nerve endings produce an inflammatory response characterized by vasodilation and plasma extravasation (13). The inflammatory response is mediated by local release of sensory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) (25).…”

“…Other mediators implicated in the pathogenesis of colitis are neuropeptides released from enteric and sensory afferent neurons (37). These peptides have been shown to modulate different aspects of mucosal function, including blood flow and secretion, and may play a role in the recruitment of granulocytes and lymphocytes and in the modulation of mast cell activation (14,18).…”

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

“…Inflammatory bowel disease is often associated with increased painful sensations in response to colorectal distension (Ritchie, 1973;Whitehead et al, 1990;Naliboff et al, 1997;Holzer, 1998;Evangelista, 2001). This hypersensitivity to mechanical stimuli has been detected in patients with ulcerative colitis as well as Crohn's disease, the two most common forms of inflammatory bowel disease (Thompson et al, 1999).…”

Highly Sensitive and Rapid Assay of Substance P and Streptolysin O in Human Serum Using Immuno-liposomes and Gramicidin Channels

“…1 SP has been implicated in pain transmission, respiration, cardiovascular control, 2 and numerous disease states, such as inflammatory disease, inflammatory arthritis, 3,4 infectious disease, 5 Alzheimer's, 6 Parkinson's, 7 and Huntington's disease. 8 Therefore, accurate measurements of SP levels in biological fluids are important for the monitoring of various characteristics of health or disease and infection.…”