The role of cholecystokinin (CCK) in the effect of dietary lipid on proximal gastrointestinal function and satiety is controversial. Recent work suggests that fatty acid chain length may be a determining factor. We investigated the mechanism by which long- and short-chain fatty acids activate jejunal afferent nerves in rats. Whole mesenteric afferent nerve discharge was recorded in anaesthetized male Wistar rats during luminal perfusion of saline, sodium oleate, and sodium butyrate (both 10 mM). Both fatty acids evoked characteristic afferent nerve responses, distinct from the mechanical response to saline, that were abolished in rats following chronic subdiaphragmatic vagotomy. The effect of oleate was abolished by the CCK-A receptor antagonist Devazepide (0.5 mg/kg), whereas the effect of butyrate persisted despite pretreatment with either Devazepide or a combination of the calcium channel inhibitors nifedipine (1 mg/kg) and the omega-conotoxins GVIA and SVIB (each 25 microg/kg). In summary, long- and short-chain fatty acids activate intestinal vagal afferents by different mechanisms; oleate acts via a CCK-mediated mechanism and butyrate appears to have a direct effect on afferent terminals.

Background & Aims-Large distensions reliably evoke sensation from the non-inflamed, nonischemic bowel, but the specialized afferent axonal structures responsible have not been

The gastrointestinal tract has an extensive intrinsic and extrinsic sensory innervation. Despite this, stimuli in the healthy gastrointestinal tract rarely reach the level of conscious perception. In contrast, sensations of abdominal discomfort and pain are common symptoms in patients with gastrointestinal disease. Symptoms include heartburn, chest pain, dyspepsia, bloating, abdominal cramps and feelings of incomplete rectal evacuation, all of which can arise in both organic (e.g. inflammatory) and functional disorders such as irritable bowel syndrome. Visceral afferent hypersensitivity is now a widely accepted mechanism which could explain many of these clinical symptoms associated with functional bowel disease and inflammatory diseases of the gut (Mayer & Raybould, 1990;Bueno et al. 1997). However, the mechanisms underlying peripheral sensitization of gastrointestinal afferents is poorly understood. Much of our understanding of the mechanisms of afferent sensitization and the modulation of painful stimuli has stemmed from studies of cutaneous pain. Sensitization of cutaneous nociceptors is thought to underlie conditions of hyperalgesia (enhanced perception of pain) and allodynia where previously non-noxious stimuli can produce pain (Heller et al. 1993). Despite the lack of detailed studies on gastrointestinal afferent sensitivity, it is generally assumed that intestinal afferents behave in a similar way, being activated andÏor sensitized by chemical mediators present within an 'inflammatory soup'. Gastrointestinal afferents terminate at different levels within the gut wall (namely

Using novel in vitro preparations of vascularly perfused rat ileum, we investigated mesenteric afferent sensitivity to vascular perfusion. Gut (GPP) and vascular (VPP) perfusion pressures were recorded simultaneously with afferent discharge (AD). After preconstriction (L-phenylephrine), capsaicin (100 microM, gut lumen) caused a transient increase in AD and a sustained fall in VPP, supporting afferent modulation of vascular tone. In turn, AD was affected by vascular perfusion rate (VPR). Increasing VPR step-wise (0.6 to 1.0, 1.4 and 1.8 ml/min) caused concomitant falls in AD, returning at 0.6 ml/min. Terminating flow (5 min) increased AD. Afferent responses were independent of changes in GPP, vascular O2, or the gut "tube" ("gut-off"). In gut-off studies, where capsaicin (100 nM ia) still reduced VPP, flow-associated falls in AD were abolished by the enzyme neuraminidase (0.2 U/ml ia or extravascularly over 20 min). In contrast, increased AD after stopped flow was unaffected. We propose that mesenteric afferents "sense" changes in vascular perfusion. The precise stimuli (pressure and/or flow) and the physiological relevance to control of local circulation remain to be determined.

Visceral afferents are the information superhighway from the gut to the central nervous system. These sensory nerves express a wide range of membrane receptors that can modulate their sensitivity. In this themes article, we concentrate on those receptors that enhance the excitability of visceral afferent neurons. Some receptors are part of a modality-specific transduction pathway involved in sensory signaling. Others, which are activated by substances derived from multiple cellular sources during ischemia, injury, or inflammation, act in a synergistic fashion to cause acute or chronic sensitization of the afferent nerves to mechanical and chemical stimuli. Such hypersensitivity is the hallmark of conditions such as irritable bowel syndrome. Accordingly, these receptors represent a rational target for drug treatments aimed at attenuating both the inappropriate visceral sensation and the aberrant reflex activity that are the foundation for alterations in bowel function.