Stress enhances abdominal contractions in response to rectal distension in rats via pathways involving central CRF and intestinal mast cells.

Because exacerbation of colitis seems to be associated with stress, we proposed evaluating the influence of stress and the involvement of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on experimental colitis in rats. Partial restraint stress was applied during 4 consecutive days, before or after intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNB) instillation (15 mg) in rats. Finally, two groups of rats were centrally injected with alpha-helical CRF-(9-41) (5 micrograms) or AVP antagonist (5 micrograms) before each session of stress. Stress was applied before or right after TNB enhanced colitis, with an increase in macroscopic and histological scores and myeloperoxidase activity, alpha-Helical CRF-(9-41) or AVP antagonist had no effect on TNB-induced colitis but enhanced the effects of stress on colitis. These results show that stress may exacerbate experimental colitis in rats and that CRF and AVP are not responsible for this effect.

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.

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The effects ofigmesine (JO 1784) and 5‐HT1A agonists (8‐OH‐DPAT, buspirone) on post‐prandial colonic transit were evaluated in conscious rats chronically fitted with an intracolonic catheter inserted into the proximal colon. Colonic transit time was evaluated by intracolonic administration of a radiolabelled marker ([51Cr]sodium chromate) and collection of the faeces, per hour, on a conveyor belt. In control studies, the colonic mean retention time was 7.8 ± 1.9 h and faecal dry matter was 50.1 ± 8.4%. Intraperitoneal treatment with igmesine (1 mg kg‐1) reduced the colonic mean retention time by 61.1 %, but was inactive at 0.1 and 0.25 mg kg‐1. Buspirone (10 mg kg‐1 IP) and 8‐OH‐DPAT (0.1 mg kg‐1) injected i.p. reduced the mean retention time. The stimulatory effect of buspirone on colonic transit was dose‐related (0.1–10 mg kg‐1). Neither igmesine, buspirone nor 8‐OH‐DPAT affected the faecal dry matter. Intracerebroventricular (i.c.v.) injection of igmesine (0.025 and 0.1 mg kg‐1) also reduced the post‐prandial mean retention time by 41.6 and 41.7%, respectively, without any effect on faecal dry matter. In contrast, intracerebroventricular injection of 8‐OH‐DPAT or buspirone had no effect on colonic mean retention time. Subcutaneous injection with BMY 14802 (1 mg kg‐1) completely prevented the igmesine‐ (0.1 mg kg‐1 i.c.v.) induced reduction of mean retention time; furthermore, spiroxatrine (0.5 mg kg‐1 s.c.) blocked both buspirone‐ (10mgkg‐1 i.p.) and 8‐OH‐DPAT‐ (0.1 mg kg‐1i.p.) induced stimulation of postpandial colonic transit. Intracerebroventricular but not i.p. injection of devazepide (10 μg kg‐1) inhibited the stimulating effect of igmesine, 8‐OH‐DPAT or buspirone on colonic transit, while L365,260 was inactive. In rats igmesine and 5‐HT1A agonists stimulate colonic transit by a mechanism involving the central release of CCK‐8s and/or the activation of supraspinal CCKergic pathways and these effects are mediated through CCKA‐type receptors.