FUNCTIONAL STUDY ON THE ROLE OF TACHYKININS IN COLONIC PERISTALTIC ACTIVITY IN MICE

Because the role of tachykinin receptors in colonic peristalsis remains incompletely understood, we studied the effect of tachykinin receptor antagonists on mouse colonic peristaltic activity. Peristaltic activity was assessed by quantifying the amplitude and interval of distension-induced pressure waves in proximal and distal colon segments of mice using a modified Trendelenburg set-up. We studied the effect of the NK1, NK2 and NK3 tachykinin receptor antagonists RP67580 (2 mM), nepadutant (1 mM) and SR142801 (0.3 mM) respectively. Gradual distension of proximal and distal colon segments induced repetitive rhythmic pressure waves which were blocked by tetrodotoxin (1 mM) and virtually abolished by hexamethonium (0.1 mM) demonstrating their neuronal origin. The NK1 receptor blocker RP67580 significantly reduced the amplitude of the pressure waves in segments of proximal (5.90.7 to 1.80.8 cmH2O, n=7) and distal (4.80.6 to 1.50.7 cmH2O, n=6) colon. RP67580 significantly reduced the interval in the proximal (667 to 876 s, n=5) but not in the distal colon. The NK2 receptor blocker nepadutant significantly reduced the amplitude (5.20.5 to 3.30.7 cmH2O, n=7) and the interval (527 to 396 s, n=7) in the proximal colon without affecting peristaltic parameters in the distal colon. Blockade of NK3 receptors by SR142801 did not affect the amplitude or interval of peristaltic waves in the proximal and distal colon. Combined blockade of NK1, NK2 plus NK3 receptors significantly reduced the amplitude in the proximal colon (6.50.9 to 1.60.8 cmH2O, n=6) and prolonged the interval (635 to 10622 s, n=6). Our study shows that mouse colonic peristaltic activity has a strong tachykininergic component that is mediated mainly by NK1 receptors and to a lesser extent by NK2 receptors. We could not demonstrate a role for NK3 receptors