Tachykinin NK₂ receptors and enhancement of cholinergic transmission in the inflamed rat colon: an in vivo motility study

Abstract

1 In the gastrointestinal tract, tachykinin NK 2 receptors are localized both on smooth muscle and nerve ®bres. NK 2 receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this e ect is unknown. In this study we investigated the e ects of atropine (1.4 mmol kg 71 , i.v.), hexamethonium (13.5 mmol kg 71 , i.v.), and nepadutant (0.1 mmol kg 71 , i.v.), a selective tachykinin NK 2 receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v 71 )-induced motility in the rat distal colon in vivo. The e ects of atropine, hexamethonium or N o -nitro-L-argininemethylester (L-NAME, 1.85 mmol kg 71 , i.v.) on [bAla 8 ]NKA(4-10) (10 nmol kg 71 , i.v.)-induced colonic contractions were also investigated. 2 When the colonic balloon was ®lled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked re¯ex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no signi®cant e ect on the distension-evoked motility. 3 Neither hexamethonium nor atropine signi®cantly reduced [bAla 8 ]NKA(4-10)-induced colonic contractions, whereas nepadutant suppressed them. Following L-NAME pretreatment, [bAla 8 ]N-KA(4-10)-induced colonic contractions were inhibited by both atropine and hexamethonium. In hexamethonium-pretreated animals, an atropine-sensitive component of [bAla 8 ]NKA(4-10)-induced colonic contractions was also evident. 4 These results indicate that the application of irritants onto the colonic mucosa induces the release of endogenous tachykinins which enhance excitatory cholinergic mechanisms through the stimulation of NK 2 receptors.

Assessment of Visceral Pain-Related Pseudo-Affective Responses to Colorectal Distension in Mice by Intracolonic Manometric Recordings

“…In order to rule out the impact of colonic motility per se on the measured balloon pressure variations, the peripherally restricted muscarinic receptor antagonist atropine methyl bromide was used to block the cholinergic excitatory input. A similar approach has been extensively used to inhibit colonic motility in mice, 4,7 rats, 8,20,29,33,37 and humans. 34 The results obtained from the current study show that atropine did not affect repetitive phasic CRD-associated balloon pressure changes, suggesting that colonic motor activity does not contribute significantly to the intraballoon pressure changes registered.…”

Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats

“…In human tissue, receptor density seems slightly higher in the colon compared to the bladder (Burcher et al 2000; Warner et al 2003). In vitro contractility studies in several species (human, rat, hamster) demonstrated NK 2 receptor mediated contraction of the bladder (Giuliani et al 1993; Palea et al 1996; Quinn et al 2004; Tramontana et al 1998; Warner et al 2003) and gastrointestinal tract (Carini et al 2001; Lecci et al 2006; Lecci et al 2004; Mule et al 2000). Moreover, the NK 2 receptor mediated bladder contractions in human SCI-induced neurogenic overactive detrusor strips were similar to those from detrusor tissue taken from normal individuals (Sellers et al 2006).…”

Inhibitory effect of Iboga-type indole alkaloids on capsaicin-induced contraction in isolated mouse rectum

“…The long-lasting contraction induced by capsaicin in the mouse rectum may be attributed to the neurokin A reactivity [33]. It has been reported that NK 2 receptor antagonists reduce the fecal output, fecal water content, and/or intestinal hypermotility induced by Salmonella enteritidis endotoxin [34], acetic acid enema [35], Escherichia coli toxin Sta, or Clostridium difficile toxin [36]. Neurokinin A is responsible for the hypermotility associated with diarrheic symptoms.…”