A new possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system

Abstract

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...

Enteric Nervous System: Neuropathic Gastrointestinal Motility

“…Evidence for ENS neurogenesis derived from indwelling stem cell populations is convincing and exciting for the subspecialty of neurogastroenterology [79][80][81][82]. Takaki et al directed their research effort to restoration of functional recto-anal inhibitory reflex connections and defecation subsequent to resection and anastomosis in a guinea pig model.…”

“…Takaki et al directed their research effort to restoration of functional recto-anal inhibitory reflex connections and defecation subsequent to resection and anastomosis in a guinea pig model. They obtained the first evidence that serotoninergic action at the 5-hydroxytryptamine 4 (5-HT 4 ) receptor subtype might be a signal for differentiation of ENS stem cells into functional neurons that become ''wired'' into a reflex circuit that restored functional colonic motility [80]. Liu and Gershon found that neurogenesis, evoked by serotonergic action at the 5-HT 4 receptor subtype, takes place in dedicated stem cell centers outside enteric ganglia in adult mouse intestine [79].…”

“…Following mitotic division, the future ENS neurons began a migratory journey of 4-6 months that terminated inside nearby ganglia. This raises the intriguing possibility that these could be the neurons that Takaki et al found occupying anastomotic sites after intestinal resection, where they differentiate into functional constituents of the recto-anal reflex circuit [80][81][82].…”

Comparison of effects of a selective 5-HT reuptake inhibitor versus a 5-HT4 receptor agonist on in vivo neurogenesis at the rectal anastomosis in rats

“…Furthermore, we found that after rectal transection local in vivo application of BDNF improved distensionevoked reflexes of the internal anal sphincter (IAS) (6). We also demonstrated that BDNF facilitates the regeneration of the reflex nerve pathway and enteric neurogenesis from neural stem cells in the granulation tissue at the anastomotic site (6). As a repairing mechanism for the neural circuit insult, we suggested that the neural stem cells have a pivotal role in enteric neurogenesis.…”

“…Recently, we reported that brain-derived neurotrophic factor (BDNF) induces the formation of enteric neural networks from murine embryonic stem (ES) cells (21). Furthermore, we found that after rectal transection local in vivo application of BDNF improved distensionevoked reflexes of the internal anal sphincter (IAS) (6). We also demonstrated that BDNF facilitates the regeneration of the reflex nerve pathway and enteric neurogenesis from neural stem cells in the granulation tissue at the anastomotic site (6).…”