Gastrointestinal motility and its enteric actors in mechanosensitivity: past and present.

Coordinated contractions of the smooth muscle layers of the gastrointestinal (GI) tract are required to produce motor patterns that ensure normal GI motility. The crucial role of the enteric nervous system (ENS), the intrinsic ganglionated network located within the GI wall, has long been recognized in the generation of the main motor patterns. However, devising an appropriate motility requires the integration of informations emanating from the lumen of the GI tract. As already found more than half a century ago, the ability of the GI tract to respond to mechanical forces such as stretch is not restricted to neuronal mechanisms. Instead, mechanosensitivity is now recognized as a property of several non-neuronal cell types, the excitability of which is probably involved in shaping the motor patterns. This brief review gives an overview on how mechanosensitivity of different cell types in the GI tract has been established and, whenever available, on what ionic conductances are involved in mechanotransduction and their potential impact on normal GI motility.

Activation of TREK-1 by morphine results in analgesia without adverse side effects.

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same µ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from µ opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the µ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

The Nav1.9 channel regulates colonic motility in mice.

The colonic migrating motor complex (CMMC) is a major pattern of motility that is entirely generated and organized by the enteric nervous system. We have previously demonstrated that the Nav1.9 channel underlies a tetrodotoxin-resistant sodium current which modulates the excitability of enteric neurons. The aim of this study was to observe the effect of loss of the Nav1.9 channel in enteric neurons on mouse colonic motility in vitro. The mechanical activity of the circular muscle was simultaneously recorded from three sites, namely, proximal, mid- and distal, along the whole colon of male, age-matched wild-type and Nav1.9 null mice. Spontaneous CMMCs were observed in all preparations. The mean frequency of CMMCs was significantly higher in the Nav1.9 null mice (one every 2.87 ± 0.1 min compared to one every 3.96 ± 0.23 min in the wild type). The mean duration of CMMCs was shorter and the mean area-under-contraction was larger in the Nav1.9 null mice compared to the wild type. In addition, CMMCs propagated preferentially in an aboral direction in the Nav1.9 null mice. Our study demonstrates that CMMCs do occur in mice lacking the Nav1.9 channel, but their characteristics are significantly different from controls. Up to now, the Nav1.9 channel was mainly associated with nociceptive neurons and involved in their hyperexcitability after inflammation. Our result shows for the first time a role for the Nav1.9 channel in a complex colonic motor pattern.

Interstitial cells of Cajal in the guinea pig gastric antrum: distribution and regional density.

Interstitial cells of Cajal (IC) have been described in the gastrointestinal (GI) tract of various species and functional studies have suggested that different classes of IC support key physiological roles in GI motility. IC express a specific cell surface tyrosine kinase receptor, c-kit. We have studied the distribution of IC in the gastric antrum of the guinea pig by immunohistochemistry using c-kit antibodies. We have identified four classes of IC on the basis of their anatomical location within the gastric wall. IC in the myenteric plexus region (IC-MY) formed a dense network; they were reduced in density at the lesser curvature compared to the greater curvature. Intramuscular IC (IC-IM) were found in the longitudinal and circular muscle layers in muscle bundles; the density of IC-IM in the circular muscle layer covaried with that of nitrergic myenteric neurons along the circumference of the antrum. Two other classes of IC are described for the first time. IC were found within septa (IC-S) that separated the circular layer into muscle bundles; IC-S were orientated perpendicular to the circular muscle from the myenteric to the submucosal region. IC in the submucosa (IC-SM) formed a loose network at the circular muscle border. These data show that the gastric antrum of the guinea pig is populated with similar classes of IC to those already described in the human and the dog. The guinea pig may therefore provide a good model for investigating the physiological roles of IC in the stomach of larger mammals.