These results indicate that activation of enteric neural 5-HT(4)-receptors promotes reconstruction of an enteric neural circuit leading to the recovery of the defecation reflex in the distal gut, and that this reconstruction involves possibly neural stem cells. These findings indicate that treatment with 5-HT(4) agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic gut disorders.

A new possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 294: G1084-G1093, 2008. First published February 28, 2008 doi:10.1152/ajpgi.00345.2007.-Moderate rectal distension elicits recto-rectal reflex contractions and simultaneous rectointernal anal sphincter reflex relaxations that together comprise the defecation reflex. Both reflexes are controlled by 1) pelvic nerves, 2) lumbar colonic nerves, and 3) enteric nervous system. The aim of the present study was to explore a novel approach to repairing the defecation reflex dysfunction by using the plasticity of enteric nervous pathways. Experiments were performed in anesthetized guinea pigs with ethyl carbamate. The rectum 30 mm oral from the anal verge was transected without damage to extrinsic nerves, and subsequent endto-end one-layer anastomosis was performed. Recovery of the defecation reflex and associated reflex pathways were evaluated. Eight weeks after sectioning of intrinsic reflex nerve pathways in the rectum, the defecation reflex recovered to the control level, accompanied with regeneration of reflex pathways. The 5-HT 4-receptor agonist mosapride (0.5 and 1.0 mg/kg) significantly (P Ͻ 0.01) enhanced the recovered defecation reflex 8 wk after surgery. Two weeks after local treatment with brain-derived neurotrophic factor (BDNF: 10 Ϫ6 g/ml) at the rectal anastomotic site, the recto-internal anal sphincter reflex relaxations recovered and some bundles of fine nerve fibers were shown to interconnect the oral and anal ends of the myenteric plexus. These results suggested a possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system with local application of BDNF.brain-derived neurotrophic factor; internal anal sphincter THE DEFECATION REFLEX, which can be elicited by moderate rectal distension, involves simultaneous recto-rectal contractions (R-R reflex) and recto-internal anal sphincter reflex relaxation (R-IAS reflex). These coordinated responses involve both extrinsic reflexes via autonomic nervous system and intrinsic reflexes via enteric nervous system (17, 19 -21, 26). The plasticity of these intrinsic reflex pathways has been shown in models involving chronic destruction of lumbar and sacral cords in guinea pig (9, 10). After the lower anterior resection for rectal cancer, however, long-lasting defecation disturbances occur in many patients owing to the impairment of reflex pathways.Recently, we have reported that the 5-HT 4 receptor agonist mosapride enhances the intrinsic R-R and R-IAS reflexes in the spinal cord injury model as well as in intact guinea pigs. This indicates that 5-HT 4 -receptor activation can enhance intrinsic R-R and R-IAS reflexes that are functionally compromised after deprivation of extrinsic nerves and that this action is mediated through intrinsic pathways (9, 10). Accordingly, following lower anterior resection, mosapride can enhance the refl...

Distension-evoked reflex of rectorectal (R-R) contractions and rectointernal anal sphincter (R-IAS) relaxations can be generated in guinea pigs through an extrinsic sacral excitatory neural pathway (pelvic nerves) as well as intrinsic cholinergic excitatory and nitrergic inhibitory pathways. The aim of the present study was to create intrinsic R-R and R-IAS reflex models by pithing (destruction of the lumbar and sacral cords; PITH) and to evaluate whether the prokinetic benzamide mosapride, a 5-HT(4) receptor agonist, enhances these reflexes. The mechanical activities of the R-R and R-IAS were recorded in the anesthetized guinea pig on days 2-9 after PITH. Although the basal rectal pressure at distension after PITH was significantly lower than control, the reflex indexes of R-R contractions and synchronous R-IAS relaxations were unchanged between days 4 and 9 after PITH. The frequency of spontaneous rectal and IAS motility were also unchanged. Immunohistochemical studies revealed that the distribution of myenteric and intramuscular interstitial cells of Cajal (ICC) were not altered after PITH. Mosapride (0.1-1.0 mg/kg iv) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indexes (maximum: 2.76) from control (1.0) 6-9 days after PITH. The 5-HT(4) receptor antagonist, GR-113808 (1.0 mg/kg iv) decreased the R-R and R-IAS reflex indexes by approximately 50% and antagonized the effect of mosapride (1.0 mg/kg iv). The present results indicate that mosapride moderately enhanced intrinsic R-R and R-IAS reflexes functionally compensated after deprivation of extrinsic nerves, mediated through endogenously active intrinsic 5-HT(4) receptors.

The enteric nervous system, the "second" brain, is an independent nervous system that structurally resembles the "first" brain. Appropriate rectal distension elicits rectal (R-R) reflex contractions and simultaneous internal anal sphincter (R-IAS) reflex relaxations that together comprise the defecation reflex. The enteric nervous system, pelvic nerves and lumbar colonic nerves control both reflexes. Using the plasticity of enteric nervous pathways, a new therapy for repairing enteric neural dysfunction could be developed. In vivo experiments were performed on guinea pigs anesthetized with ethyl carbamate. We performed either a lower anterior resection as used for rectal cancer, without damaging the extrinsic nerves or a resection of a 2-cm segment of distal colon, 30 mm orally from the anal verge, with subsequent end-to-end one layer anastomosis of the exposed ends. The recovery of the defecation reflex was found to be the same in both the rectal transection and distal colonic resection procedures. Eight weeks after sectioning the intrinsic reflex nerve pathways in the rectum, the defecation reflex recovered to control levels, accompanied by a regeneration of the reflex pathways. The 5-HT(4) receptor agonist, mosapride (0.5 and 1.0 mg/kg), significantly (P<0.01) enhanced the recovered defecation reflex at this stage. Two weeks after local treatment with brain-derived neurotrophic factor (BDNF: 10(-6) g/ml) at the rectal anastomotic site, the R-IAS reflex relaxations recovered and some bundles of fine nerve fibers were able to be seen interconnecting the oral and anal ends of the myenteric plexus. Also surprisingly, new neurons were found to have generated from neural stem cells at the anastomotic ends. These new neurons had constructed mature enteric neural networks including ganglionic-like structures eight weeks after surgery. These results revealed the plasticity of enteric neurons, allowing the proposal of a new therapy for repairing enteric neural dysfunction at least after surgery.

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT4 receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT4 receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT4 receptors which may be post-synaptically located in the myenteric plexus of the anorectum.

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