Cholinergic transmission to colonic circular muscle of children with slow‐transit constipation is unimpaired, but transmission via NK₂ receptors is lacking

Abstract

Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow-transit constipation (STC) have reduced TK-immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK-immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA-evoked contractions in adult and STC colon. Hyoscine (2 micromol L-1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 micromol L-1) significantly depressed EFS-evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK-immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.

Impaired colonic motility and reduction in tachykinin signalling in the aged mouse

“…In addition, both a reduction in the density of tachykininimmunoreactive nerve fibres in human colonic circular muscle (Porter et al, 1998) and decreases in tachykininsignalinghavebeen observed in patients with slow transit constipation consistent with tachykinins having apro-kinetic effect. (King et al, 2010;Stanton et al, 2003).…”

Distribution pattern of tachykinin NK2 receptors in human colon: Involvement in the regulation of intestinal motility

“…The results of many pharmacological studies have combined to show that TKs-induced contraction via NK2r is reduced in patients affected by constipation, diverticulosis, and inflammatory bowel disease (Al-Saffar and Hellstrom, 2001;Liu et al, 2002;Cao et al, 2004a,b; for reviews, see Lecci et al, 2004Lecci et al, , 2006. Moreover, in colonic circular muscle of children with slow-transit constipation, neuromuscular transmission via NK2r is lacking (Stanton et al, 2003).…”

“…The NK2r antagonists MEN10376 and GR94800 reduced the tetrodotoxin-sensitive spontaneous motility of the circular muscle layer (Cao et al, 2004b). In the circular muscle layer the NK2r antagonist SR48968 greatly decreases the atropine-sensitive EFS-induced contractions, suggesting that NK2r might be involved in the prejunctional neuronal cholinergic processes modulating colonic motility (Stanton et al, 2003;Maselli et al, 2004). The results of many pharmacological studies have combined to show that TKs-induced contraction via NK2r is reduced in patients affected by constipation, diverticulosis, and inflammatory bowel disease (Al-Saffar and Hellstrom, 2001;Liu et al, 2002;Cao et al, 2004a,b; for reviews, see Lecci et al, 2004Lecci et al, , 2006.…”

Characterization of motor patterns in isolated human colon: are there differences in patients with slow-transit constipation?

“…There is also evidence that the interval between CMCs is reduced in the transverse colon and splenic flexure (9). Other studies have demonstrated reductions in specific neurochemical classes of myenteric neurons in STC patients (4,15,21,32), in addition to reduced density of pacemaker cells (16) or specific types of neuromuscular transmission (31). Whether anatomical or functional changes in the large intestine of STC patients represents a cause or an effect of STC is not fully clear.…”