Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress

Abstract

Otilonium bromide (OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome (IBS). Its efficacy has been attributed to the block of L‐ and T‐type Ca2+ channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress (WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP‐, NK1r‐, nNOS‐, VIP‐, and S100β‐immunoreactivity (IR) and the increase in CGRP‐, and CRF1r‐IR. On the contrary, OB does not affect the increase in CRF2r‐IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT‐IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L‐type Ca2+ channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions.

The effects of three novel probiotics isolated from the Korean fermented food Kimchi on the stress-induced defecation of rats

“…The efficacy of this test is confirmed by the development of an immediate hyperalgesia [18], the inhibition of small intestinal transit, the stimulation of large intestinal activity and the incidence of an increased fecal excretion [15]. Also, it was recently demonstrated that rats underwent testing to the restrain stress presented a low-grade mucosal inflammation, with a significant increase in mast cells and eosinophilic granulocytes [19,20], that is seen to have overlapped on what is described in colonic biopsies of IBS patients [21].…”

Experimental Models of Irritable Bowel Syndrome and the Role of the Enteric Neurotransmission

“…Probably thanks to this multi-target activity, OB effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients (71). Conversely, OB tested in experimental models of visceral sensitivity, at least in WRS, was less active as compared to the other agents previously reviewed (20). Another antispasmodic such as pinaverium bromide endowed with L-type calcium channel blocker and antimuscarinic activity improved motility disorders and consequently reduced stool problems in IBS patients.…”

“…The efficacy of this test is confirmed by the development of an immediate hyperalgesia, quantifiable in colon-rectal distention (CRD) number (18), the inhibition of small intestinal transit, the stimulation of large intestinal activity and increased fecal excretion (17). We recently demonstrated that rats underwent to the WRS presented a low-grade mucosal inflammation with a significant increase in mast cells and eosinophylic granulocytes (19,20) that overlapped that described in colonic biopsies of IBS (21). Moreover, these animals showed important changes in the glial cells, in inhibitory and excitatory neurotransmitters and receptors that were interpreted as responsible for the dysmotility and hypersensitivity present in IBS patients.…”

“…Central injection of CRF can reproduce behavioral and physiological reactions similar to those seen in response to acute psychological stress (42,43), and inhibition of CRF-mediated responses by antagonists (43,44) or in knockout animals results in a decrease of the animals' answer to stress (45,46). However, recent experimental studies point to an equally important contribution of the gut CRFr1-2/CRF signaling to the GI stress response (20,47). In the GI tract the CRFr are expressed by enteric neurons (Fig.2) and mucosal cells (19,20,(48)(49)(50)(51)(52) and an upregulation of these receptors has been reported in the colon of male Wistar rats underwent to delayed stress-induced visceral hyperalgesia (37,44) and WRS (19,20).…”

“…However, recent experimental studies point to an equally important contribution of the gut CRFr1-2/CRF signaling to the GI stress response (20,47). In the GI tract the CRFr are expressed by enteric neurons (Fig.2) and mucosal cells (19,20,(48)(49)(50)(51)(52) and an upregulation of these receptors has been reported in the colon of male Wistar rats underwent to delayed stress-induced visceral hyperalgesia (37,44) and WRS (19,20).…”