What activates visceral afferents?

Abstract

Vagal and spinal afferents represent the information superhighways that convey sensory information from the gut to the central nervous system. These afferents are sensitive to both mechanical and chemical stimuli. Vagal afferents terminate in the muscle layers and in the mucosa. Muscle afferents are activated at physiological levels of distension and during peristalsis. In contrast, spinal afferents encode supraphysiological levels of intestinal pressure. Vagal and spinal afferents also express a wide range of membrane receptors to a variety of chemical mediators generated from both within and outside the gut wall. Some of these receptors are part of a modality specific transduction pathway involved in sensory signalling from the gut lumen to vagal afferent endings in the mucosa. Others, which are activated by substances derived from multiple cellular sources during ischaemia, injury, or inflammation act in a synergistic way to cause acute or chronic sensitisation of the afferent nerves to mechanical and chemical stimuli. Understanding the mechanisms that underlie hypersensitivity may have implications for the pharmaceutical approach to the treatment of functional bowel disorders like irritable bowel syndrome.

Figure 1

Whole nerve mesenteric afferent recording from the rat jejunum showing a biphasic pattern of mechanosensitivity during ramp distension to 60 mmHg. The top trace is intrajejunal pressure, the middle trace shows a sequential rate histogram of afferent firing frequency, and below that are snapshots of the neurogram taken at baseline and during the low and high threshold phases of the response to distension. Note the prominent increase in firing at low levels of distension is a reflection of low threshold mechanosensitive afferents, whose response plateaus until intrajejunal pressure reaches threshold for activation of high threshold afferents. Reprinted from Booth et al (Gastroenterology 2001;121:358–69)[Medline] with permission from the American Gastroenterological Association.

Figure 2

Some of the potential receptor mechanisms underlying activation and sensitisation of gastrointestinal sensory afferents. Mediators such as serotonin (5-HT) cause activation whereas others, like PGE2, sensitise visceral afferent responses to other stimuli. Others, for example adenosine (Adeno), cause both stimulation and sensitisation, possibly through distinct receptor mechanisms. Bradykinin has a self sensitising action, stimulating discharge through activation of phospholipase C (PLC) and enhancing excitability via prostaglandins (PGs) following activation of phospholipase A2 (PLA2). Inflammatory mediators can be released from different cell types (such as sympathetic nerves, mast cells, and blood vessels) present in or around the afferent nerve terminal. 5-HT, adenosine triphosphate (ATP) and capsaicin (Cap) can directly activate non-selective cation channels (NSCCs) while adenosine, histamine, prostaglandins (not PGE2), and proteases such as mast cell tryptase (Tryp) and thrombin (Thro) act on G-protein coupled receptors leading to a Ca2+ dependent modulation of ion channel activity. Sensitisation, however, may be mediated by raised intracellular cyclic adenosine 3', 5'-monophosphate (cAMP). Adenosine and PGE2 can generate cAMP directly through G-protein-coupled stimulation of adenylate cyclase (AC). In contrast, histamine may act indirectly through the generation of prostaglandins (8). The actions of cAMP downstream may involve modulation of ion channels, interaction with other second messengers (eg Ca2+), or even changes in receptor expression. Other abbreviations: protease activated receptors (PARs), cyclooxygenase-1 and 2 (COX-1, COX-2), arachidonic acid (AA), diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3). Reprinted from Kirkup et al (Am J Physiol Gastrointest Liver Physiol 2001;280:G787–94)[Abstract/Free Full Text] with permission from the American Physiological Society.