Modulation of peristalsis by NK₃ receptor antagonism in guinea‐pig isolated ileum is revealed as intraluminal pressure is raised

Abstract

1. NK(3) tachykinin receptors mediate slow excitatory transmission in the enteric nervous system and play a role in reflexes induced by the intestinal stretch or mucosal compression. However, there is little evidence to suggest that these receptors are important in peristalsis. We have examined the effects of the NK(3) receptor antagonist, talnetant, on peristalsis in guinea-pig isolated ileum induced by optimal and by supra-maximal distension pressures. 2. At the guinea-pig NK(3) receptor, talnetant was shown to have high affinity (pK(B) 8.8) and selectivity over the guinea-pig NK(1) and NK(2) receptors. 3. Peristaltic waves in the ileum elicited by optimal distension pressures (1-3 cmH(2)O) were unaffected by talnetant at a supra-maximal concentration (250 nm). 4. Distension at a higher pressure (4 cmH(2)O) induced peristalsis in which there was incomplete closure of the lumen during each peristaltic wave and an increase in the periods of inactivity observed between bursts of peristaltic activity. The addition of talnetant (250 nm) increased the number of peristaltic events by reducing these periods of inactivity and thus, increased the productivity of the peristaltic reflex. 5. The data suggest that NK(3) receptors are not involved in the modulation of peristaltic movements by physiological stimuli, but they may have a role in modulation of reflexes in extreme or pathological conditions.

Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome

“…Similar findings have been reported for the guinea pig distal colon . In particular, in guinea pigs, NK3 receptors have been demonstrated to play a role in the modulation of ileum peristalsis but only when elicited by high level of pressure distension …”

“…39 In particular, in guinea pigs, NK3 receptors have been demonstrated to play a role in the modulation of ileum peristalsis but only when elicited by high level of pressure distension. 40 In the rabbit distal colon, NK2 receptor antagonists accelerate or inhibit the velocity of propulsion, depending on their concentration, respectively through an indirect neuronal inhibition of release of nitric oxide in the first case and a direct postjunctional blockade of NK2 receptors in the second case. 41 Along the same line, NK3 receptor antagonists induce a prokinetic effect at low concentrations and an inhibitory effect at high concentrations.…”

Effect of the NK3 receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans

“…Consequently, a hypothesis was developed that NK 3 receptor antagonists, which have little or no activity on normal gastrointestinal motility, could reduce the effects of tachykinins released from enteric intrinsic primary afferent neurons (IPANs), following activation by a ‘supra‐maximal’ or noxious stimulus 17 . In addition, to modulating C‐fibre nerve terminal sensitivity, these effects included an ability to influence the sensitivity of connecting IPANs, influencing enteric nerve sensitivity and prolonging peristalsis during periods of intense intestinal distension 18 …”

“…17 In addition, to modulating C-fibre nerve terminal sensitivity, these effects included an ability to influence the sensitivity of connecting IPANs, influencing enteric nerve sensitivity and prolonging peristalsis during periods of intense intestinal distension. 18 Thus, the general aim of this study was to evaluate the significance of these findings in humans in two separate centres using talnetant (SB223412), an orally active, competitive, non-peptide, selective NK 3 receptor antagonist which was previously demonstrated to be effective as an intestinal antinociceptive agent in animal models. 15,17 The specific aim of the present study was to compare the effects of 25 and 100 mg doses of talnetant vs placebo on rectal sensation and compliance during standardized distensions with the barostat in healthy volunteers.…”

Differential role of tachykinin NK3 receptors on cholinergic excitatory neurotransmission in the mouse stomach and small intestine

“…This correlates well with the assumption that tachykinin NK 3 receptors have a minor function in normal gut reflexes, as deduced from the lack of effect of NK 3 receptor antagonists on intestinal peristalsis in the guinea pig, pig and rat ( Holzer et al ., 1998 ; Schmidt and Hoist, 2002 ; Shafton et al ., 2004 ). Interestingly, Sanger et al . (2007) recently confirmed these findings but additionally showed that tachykinin NK 3 receptors do modulate the peristaltic reflex but only at intestinal pressures that are associated with a defensive behaviour of the intestine.…”