Recent advances in enteric neurobiology: mechanosensitive interneurons

Until recently, it was generally assumed that the only intrinsic sensory neuron, or primary afferent neuron, in the gut was the after-hyperpolarizing AH/Type II neuron. AH neurons excited by local chemical and mechanical stimulation of the mucosa appear to be necessary for activating the peristaltic reflex (oral excitation and anal inhibition of the muscle layers) and anally propagating ring like contractions (peristaltic waves) that depend upon smooth muscle tone. However, our recent findings in the guinea-pig distal colon suggest that different neurochemical classes of interneuron in the colon are also mechanosensitive in that they respond directly to changes in muscle length, rather than muscle tone or tension. These interneurons have electrophysiological properties consistent with myenteric S-neurons. Ascending and descending interneurons respond directly to circumferential stretch by generating an ongoing polarized peristaltic reflex activity (oral excitatory and anal inhibitory junction potentials) in the muscle for as long as the stimulus is maintained. Some descending (nitric oxide synthase +ve) interneurons, on the other hand, appear to respond directly to longitudinal stretch and are involved in accommodation and slow transit of faecal pellets down the colon. This review will present recent evidence that suggests some myenteric S interneurons, in addition to AH neurons, behave as intrinsic sensory neurons.     

Differences in the levels of Sonic hedgehog protein during early foregut development caused by exposure to Adriamycin give clues to the role of the<Emphasis Type="Italic"> Shh</Emphasis> gene in oesophageal atresia

Sonic hedgehog (Shh) protein is a signalling molecule that is important for defining patterning in the development of vertebrates. Shh has been shown to be involved in the morphogenesis of many organ systems such as notochord, floor plate and limbs and in the development of the left-right axis in vertebrates. In this study we show that high levels of protein occur during the initial period of foregut differentiation into trachea and oesophagus, and that low levels of Shh protein are seen during early development of the foregut where oesophageal atresia and/or tracheo-oesophageal fistula ensue. These studies show that Shh protein is expressed in the rat foregut during embryogenesis, and its level declines as the embryo approaches birth. In adriamycin-treated rats the level of Shh protein expression is very low without any time-dependent changes. These results are consistent with the hypothesis that adriamycin influences the Shh signalling pathway, resulting in disruption of normal development of the foregut.     

The development of the proximal oesophageal pouch in the adriamycin rat model of oesophageal atresia with tracheo-oesophageal fistula

This study examined the morphological development of the proximal oesophagus in the Adriamycin-induced rat model of oesophageal atresia. The proximal oesophageal segment in oesophageal atresia with tracheo-oesophageal fistula (OA\TOF) has been assumed to be of similar embryological origin to the distal oesophagus. However, recent research using the Adriamycin model of OA\TOF has indicated that these structures may have a different origin. Time-mated Sprague-Dawley rats were administered either Adriamycin intraperitoneally or saline of an equivalent volume between days 6–9 of gestation. The rats were sacrificed between days 11–19 of gestation, their embryos removed and histologically sectioned. These sections were analysed to observe the morphological changes occurring in the proximal foregut. The proximal oesophageal pouch first appeared on day 15.25 as a dorsal outpouching of the proximal foregut immediately cranial to an area of apoptosis in the dorsal epithelium of the distal pharynx. It elongated through a process of cellular proliferation until it was clearly formed on day 16. Relatively little growth occurred from days 17–19. In the rat developing oesophageal atresia, the proximal oesophageal pouch has an origin different to that of the distal oesophagus. This study may explain the difference in immunohistological properties and intrinsic nervous supply between the proximal and distal oesophageal segments in oesophageal atresia.     

Intussusception

In the previous two parts of this review on intussusception, the diagnosis and management of symptomatic, idiopathic ileocolic and ileoileocolic intussusceptions, which are considered to result from hyperplasia of lymphoid tissue in the distal ileum, were discussed. In this third part, those intussusceptions with an identifiable cause including pathologic lead point, those due to gastrojejunostomy or other feeding tubes, and those that are seen in the postoperative period as well as those that may be asymptomatic or may reduce spontaneously (usually limited to the small bowel) are discussed.     

Abnormalities of the vertebral column and ribs associated with anorectal malformations

Lumbosacral vertebral abnormalities are a common association of anorectal malformations (ARMs) and are one of the determinants of the eventual level of fecal continence that can be achieved. This study used a fetal rat model to investigate the spectrum of axial skeletal maldevelopment that may occur with ARMs. Time-mated pregnant rats received 125 mg/kg of 1% ethylenethiourea (ETU) (experimental group) or vehicle only (control). Their fetuses were examined for external malformations and prepared for staining of their skeletons using Alcian blue and Alizarin red S. ARMs developed in 67/68 (98%) of ETU-exposed fetuses, of which 28 (42%) also developed rachischisis, mainly involving the lumbosacral vertebrae. No skeletal abnormality was found in control fetuses. ETU-exposed fetuses with ARMs and rachischisis had abnormal ossification of the vertebral centrum, abnormal fusion between the neural arches of vertebrae, localized narrow or interrupted thoracic vertebral canal, a widely open vertebral canal in the lumbosacral area (rachischisis), and absence of the lower two sacral and coccygeal vertebrae. Rib abnormalities included absence of two to three floating ribs, abnormal fusion of adjacent proximal segments, and abnormal ramification, irregularity, and angulation of their distal segments. The vertebral and rib abnormalities found in ETU-exposed fetuses with ARMs but no rachischisis were much less severe. In addition to the lumbosacral anomalies that are common with ARMs, severe abnormalities of the thoracic vertebrae and their corresponding ribs may occur also. Fetuses with both ARM and rachischisis tend to have more extensive and severe vertebral and rib anomalies. These observations imply a possible common aetiology for ARMs and vertebral anomalies and are consistent with our understanding of the perceived role of the notochord in axial development.