No abstract

Small intestinal movements depend on the composition of the chyme with mixing predominating at high nutrient levels and propulsion being prevalent at low nutrient levels. The mechanisms coupling nutrients to motility are unknown. We used computer analysis of video recordings of isolated guinea-pig duodenum, jejunum and ileum to examine movements induced by a fatty acid, decanoic acid. Increasing intraluminal pressure past a threshold using control saline consistently evoked propulsive reflexes: lumen-occluding constrictions appeared at the oral end propagating at 20.4 ± 2.4 mm s −1 (mean ± S.D., jejunum) to the anal end before being repeated until the intraluminal pressure was returned to control. Subthreshold pressure increases sometimes evoked a transient series of constrictions appearing at the oral end and propagating anally at 18.4 ± 4.7 mm s −1 (jejunum). At basal pressures, decanoic acid dose-dependently induced motor activity consisting of 40-60 s episodes of constrictions separated by 40-200 s periods of quiescence and lasting up to 2 h. Five contraction patterns were identified within episodes including localized stationary constrictions; constrictions that propagated slowly (5-8 mm s −1 ) for short distances orally or anally; and constrictions that propagated orally or anally for the length of the preparation at 14-20 mm s −1 . Decanoic acid induced motor activity was reversibly abolished by tetrodotoxin (3 µM), hyoscine (1 µM) and hexamethonium (100 µM ), but was insensitive to blockade of P2 purinoceptors by PPADS (60 µM). Thus, decanoic acid induces motor activity equivalent to segmentation in guinea-pig small intestine in vitro and this depends on intrinsic neural pathways.

Responses of myenteric AH and S neurons to local application of chemicals to the mucosa of the guinea pig small intestine were obtained using conventional intracellular recording techniques. Preparations were dissected to reveal the myenteric plexus over one-half of the circumference of the gut with intact mucosa on the the half. Neurons were impaled within the exposed one-half, whereas potential stimulants, in buffered saline, were transiently applied to the mucosa, 1-1.5 mm circumferential from the impalement. The stimulants elicited action potentials (AP) in AH neurons that did not arise from synaptic activity. AH neurons also responded with slow excitatory postsynaptic potentials (EPSP). S neurons were activated synaptically, via fast and slow EPSP, but not nonsynaptically. Mucosal application of solutions of a low pH (3-5) or a high pH (9-11) were both effective stimulants. Solutions of a neutral pH, which was also a control for mild mechanical stimulation, were usually ineffective. Both a short-chain fatty acid, acetate (pH 7.2), and 5-hydroxytryptamine elicited responses in each neuronal type. We conclude that myenteric AH neurons of the guinea pig distal ileum are primary afferent neurons that respond to a variety of mucosally applied chemical stimuli with burst of AP. In addition, the physiologically evoked transmission of slow EPSP to AH neurons suggests that primary afferent neurons interconnect in a self-reinforcing network. S neurons are second or higher order neurons in the reflex pathways.

Isolated longitudinal muscle‐myenteric plexus preparations from guinea‐pig ileum were used to investigate the activity of myenteric neurons when the tissue was stretched in the circumferential direction. Membrane potentials were recorded via flexibly mounted intracellular recording electrodes containing Neurobiotin in 1 M KCl. The preparations were stretched to constant widths (+20 % and +40 % beyond slack width). Multipolar neurons (Dogiel type II morphology) discharged spontaneous action potentials and proximal process potentials during maintained stretching, three of twenty‐one at +20 % stretch and seven of nine at +40 % stretch. At the maximum extent of stretch tried, +40 % beyond slack tissue width, action potentials in Dogiel type II neurons occurred at 10‐33 Hz. Neurons with other morphologies were all uniaxonal. Some displayed spontaneous fast EPSPs or action potentials, three of forty‐one at +20 % stretch and seven of nineteen at +40 % stretch. In seven of eight Dogiel type II neurons, action potentials or proximal process potentials persisted when membrane hyperpolarization was imposed via the recording electrode. Action potential discharge was abolished by hyperpolarization in seven of nine uniaxonal neurons; the exceptions were two orally projecting neurons. Dogiel type II and uniaxonal neurons were classified as rapidly accommodating if they discharged action potentials only at the beginning of a 500 ms intracellular depolarizing pulse and slowly accommodating if they discharged for more than 250 ms. For Dogiel type II neurons, three of thirteen were slowly accommodating at +20 % stretch and two of four at 40 % stretch. For uniaxonal neurons the corresponding data were twelve of twenty‐six and fifteen of nineteen neurons. The slowly accommodating state was associated with increased cell input resistance in uniaxonal neurons. The spontaneous action potential discharge in Dogiel type II and uniaxonal neurons ceased when the muscle was relaxed pharmacologically by nicardipine (3 μM) or isoprenaline (1 μM), although the applied stretch was maintained. At the same time, evoked spike discharge became rapidly accommodating We conclude that many Dogiel type II neurons, and possibly some orally projecting uniaxonal neurons, are intrinsic, stretch‐sensitive, primary afferent neurons that respond to muscle tension with sustained action potential discharge.

Gastrointestinal (GI) side-effects of chemotherapy are a debilitating and often overlooked clinical hurdle in cancer management. Chemotherapy-induced constipation (CIC) and Diarrhea (CID) present a constant challenge in the efficient and tolerable treatment of cancer and are amongst the primary contributors to dose reductions, delays and cessation of treatment. Although prevalence of CIC is hard to estimate, it is believed to affect approximately 16% of cancer patients, whilst incidence of CID has been estimated to be as high as 80%. Despite this, the underlying mechanisms of both CID and CIC remain unclear, but are believed to result from a combination of intersecting mechanisms including inflammation, secretory dysfunctions, GI dysmotility and alterations in GI innervation. Current treatments for CIC and CID aim to reduce the severity of symptoms rather than combating the pathophysiological mechanisms of dysfunction, and often result in worsening of already chronic GI symptoms or trigger the onset of a plethora of other side-effects including respiratory depression, uneven heartbeat, seizures, and neurotoxicity. Emerging treatments including those targeting the enteric nervous system present promising avenues to alleviate CID and CIC. Identification of potential targets for novel therapies to alleviate chemotherapy-induced toxicity is essential to improve clinical outcomes and quality of life amongst cancer sufferers.

The enteric nervous system regulates intestinal motility. It contains intrinsic sensory neurones, several types of interneurones and excitatory and inhibitory motor neurones. This review summarizes our knowledge of motor neurones and interneurones in simple motility reflex pathways (ascending and descending excitation, descending inhibition) and it focuses on guinea-pig ileum. Excitatory circular muscle motor neurones contain choline acetyltransferase (ChAT) and tachykinins and project orally 0.5-10 mm. They transmit via muscarinic acetylcholine receptors and tachykinins acting at NK1 and NK2 receptors. Inhibitory circular muscle motor neurones contain nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP), project anally up to 25 mm and transmit via ATP, nitric oxide and/or VIP. Ascending interneurones project up to 10 mm orally and contain ChAT and tachykinins. They transmit to each other via ACh at nicotinic receptors (nAChR), but to excitatory motor neurones via both nAChR and NK3 receptors. There are at least three types of descending interneurones and one transmits to inhibitory motor neurones via ATP acting at P2X receptors. NOS-containing descending interneurones receive input via P2Y receptors from other interneurones. Transmission to and from the other descending interneurones (ChAT/5-HT, ChAT/somatostatin) is yet to be characterized.

Colonic migrating motor complexes (CMMCs) are spontaneous, anally propagating constrictions, repeating every 3-5 min in mouse colon in vitro. They are regulated by the enteric nervous system and may be equivalent to mass movement contractions. We examined postnatal development of CMMCs and circular muscle innervation to gain insight into mechanisms regulating transit in the maturing colon. Video recordings of mouse colon in vitro were used to construct spatiotemporal maps of spontaneous contractile patterns. Development of nitric oxide synthase (NOS) and cholinergic nerve terminals in the circular muscle was examined immunohistochemically. In adults, CMMCs appeared regularly at 4.6 +/- 0.9-min intervals (n = 5). These intervals were reduced by inhibition of NOS (2.7 +/- 0.2 min; n = 5; P < 0.05). CMMCs were abolished by tetrodotoxin (n = 4). CMMCs at postnatal day (P)10 were indistinguishable from adult. At birth and P4, CMMCs were absent. Instead, small constrictions that propagated both orally and anally, "ripples," were seen. Ripples were unaffected by tetrodotoxin or inhibition of NOS and were present in Ret(-/-) mice (which lack enteric neurons) at embryonic day 18.5. In P6 mice, only ripples were seen in control, but NOS inhibition induced CMMCs (n = 8). NOS terminals were abundant in the circular muscle at birth; cholinergic terminals were sparse but were common by P10. In mouse, myogenic ripples are the only mechanism available to produce colonic transit at birth. At P6, neural circuits that generate CMMCs are present but are inhibited by tonic activity of nitric oxide. Adult patterns appear by P10.

No abstract