Reversal of CRF‐ and dopamine‐induced stimulation of colonic motility by CCK and igmesine (JO 1784) in the rat

Abstract

The role of dopamine in the genesis of corticotropin releasing factor (CRF)‐ and emotional stress (ES)‐induced stimulation of colonic motility, as well as the mechanism of antagonistic action of cholecystokinin octapeptide (CCK‐8s) and igmesine (a σ receptor ligand, formerly JO 1784) on dopamine‐induced colonic hypermotility, have been investigated in the rat. ES and i.c.v. injection of CRF (0.5 μg kg−1) increased the frequency of colonic spike bursts by 63% and 114%, respectively. Prior i.c.v. administration of (+)‐SCH 23390 (a D1 receptor antagonist, 10 μg kg−1) significantly (P < 0.05) reduced the CRF‐ and ES‐induced increase in colonic spike burst; whereas, sulpiride (a D2 receptor antagonist, 10 μg kg−1) blocked the CRF‐induced stimulation of colonic spike bursts but had no effect on the colonic response to stress. I.c.v. injection of dopamine (100 μg kg−1), increased colonic spike burst frequency by 54%. (+)‐SKF 38393 (5 μg kg−1), a selective D1 receptor agonist, and quinpirole (5 μg kg−1), a selective D2 receptor agonist, increased colonic spike burst frequency by 71% and 70% respectively. CCK‐8s (0.1 μg kg−1) and igmesine (0.1 μg kg−1) injected i.c.v. completely prevented the stimulatory effects of dopamine, (+)‐SKF 38393 and quinpirole. Previous i.c.v. injection of devazepide, a CCKA receptor antagonist, (10 μg kg−1) antagonized the inhibitory effects of both CCK‐8s and igmesine injected i.c.v. on dopamine‐induced colonic hyperkinesia. These results show that CRF stimulates colonic motility through activation of central dopaminergic mechanisms in response to stress; furthermore, CCK‐8s inhibits dopamine‐induced colonic hyperkinesia through a mechanism involving D1 and D2 receptors. The σ receptor ligand igmesine, blocks the CRF‐ and ES‐induced colonic hyperactivity via an interaction with central CCK mechanisms.

Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats

“…Both intracerebroventricular injection of CRF and stress peripherally promote the release of 5-HT from enterochromaffin cells and enteric serotonergic neurons and lead to the enhancement of colonic motility (23). Stress also activates dopamine metabolism in mesolimbic and mesocortical structures, as well as in striatum, and the release of CRF due to stress exposure involves the activation of central dopaminergic neurons (12). Another neurotransmitter that has an antistress effect is vasopressin (AVP), which is coexpressed with CRF in parvocellular neurons of the PVN.…”

Sigma receptors [σRs]: biology in normal and diseased states

“…They stimulate the postprandial colonic motility in dogs by acting selectively on sigma receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism ( 1007 ). Other findings indicate that σR ligand igmesine, blocks the corticotropin releasing factor and emotional stress-induced colonic hypermotility also via an interaction with central cholecystokinin octapaptide mechanisms ( 1008 , 1009 ).…”