Intrinsic Neural Control of Propulsion, Storage and Slow Transit in the Large Intestine.
AuthorDickson, Eamonn James
AdvisorSmith, Terence K
Biochemistry and Molecular Biology
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The experiments described in this dissertation have examined how the enteric nervous system regulates specific aspects of gastrointestinal motility. We have identified, despite over 100 years of gastrointestinal research, a new intrinsic neural reflex that appears to underlie slow transit and accommodation in the large bowel. Using electrophysiological techniques we demonstrate that circumferential stretch generates ongoing oral excitatory and anal inhibitory junction potentials in the circular muscle (CM) of both the guinea pig distal and primate sigmoid colons. This activity has been referred to as ongoing peristaltic reflex activity. The sensory elements underlying the repetitive firing of ascending excitatory and descending inhibitory neuronal pathways lie in the CM, in close opposition to the myenteric plexus. Mechanosensitive ion channels present on the sensory elements are likely to be responsible for the transduction of the circumferential stretch.In the guinea pig distal and primate sigmoid colons, application of longitudinal stretch inhibited all junction potentials in both species. Inhibiting nitric oxide (NO) synthesis with N-ω-nitro-L-arginine (100 μmol/L) completely reversed the inhibitory effects of longitudinal stretch suggesting that nitric oxide (NO) inhibited interneurons controlling peristaltic circuits. Ca2+ imaging in preparations that were stretched in both axes revealed ongoing firing in nNOS +ve descending neurons, even when synaptic transmission was blocked. Inhibitory postsynaptic potentials could be evoked in mechanosensitive interneurons and subsequentially blocked by N-ω-nitro-L-arginine (100 μmol/L). Video imaging analysis revealed that full guinea pig colons were 158.1 ± 6.1% longer than empty colons. Furthermore, as each pellet was expelled, the colon shortened and pellet velocity increased exponentially (full 0.34, empty 1.01 mm s-1). Colonic elongation (140% of its empty slack length) applied oral to the recording site abolished circumferentially activated polarized reflexes, whereas anal elongation significantly increased the frequency and amplitude of ongoing peristaltic activity. Oral elongation inhibited the excitation produced by anal elongation; blocking NO synthesis reversed this inhibitory effect. This suggests that longitudinal stretch excites specific mechanosensitive ascending and descending interneurons, leading to activation of polarized reflexes. The dominance of the descending inhibitory reflex leads to slowed emptying of pellets in a naturally elongated colon. Electrophysiological studies in the empty murine colon revealed that each colonic MMC involves a stochastic process, whereby the firing of many myenteric ascending and descending interneurons becomes temporally synchronized. When a fecal pellet is introduced into the colon, it activates local mucosal reflexes, which release 5-HT from enterochromaffin cells, and stretch reflexes that determine the site of origin and propagation of the CMMC, facilitating propulsion.Collectively, these studies demonstrate that in addition to AH sensory neurons; specific interneurons within the enteric nervous system of the large bowel are mechanosensitive. These interneurons appear to regulate propulsion along the colon, while others promote slow transit and accommodate of fecal pellets.