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Some of the challenges in drug development for irritable bowel syndrome
  1. E A MAYER
  1. UCLA/CURE Neuroenteric Disease Program
  2. Departments of Medicine and Physiology
  3. UCLA School of Medicine, Los Angeles, CA 90024, USA
  1. Dr E A Mayer, UCLA/CURE Neuroenteric Disease Program, GLA VA HS, Bldg. 115, Room 223, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. emayer{at}

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If one accepts the concept that enhanced perception of visceral stimuli plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (and not everybody does!1 ,2), identification of drugs which can normalise this enhanced perception should be a major effort in the search for effective IBS medications. Enhanced perception of different physiologically occurring gut stimuli can result from numerous mechanisms, including such fundamentally different but possibly interrelated processes as changes in sensory transmission (in the periphery or centrally), alterations in endogenous pain modulation, or even changes in gut directed attentional mechanisms.3Any of these mechanisms alone or in combination could produce some of the most prevalent clinical manifestations of visceral hypersensitivity in IBS: sensations of abdominal fullness (in the absence of excessive distension), abdominal pain (in the absence of detectable tissue injury), sigmoid tenderness during palpation or during endoscopic examination, or the sensation of incomplete rectal evacuation (in the absence of a full rectum).

Based on several studies in the rat, demonstrating that acute mucosal inflammation can produce sensitisation of primary afferents as well as dorsal horn neurones thereby resulting in acute visceral hyperalgesia,3 the concept of targeting and testing candidate drugs for their visceroanalgesic potential has been widely accepted as a worthwhile endeavour by industry and academia alike.4 The strategies pursued by optimists in this field are variations of the following sequence: (1) identify receptors or ion channels on visceral afferent neurones; (2) select compounds targeted at these membrane proteins; (3) evaluate candidate compounds for their ability to reduce behavioural responses of the rat or other rodents to colorectal distension (ideally in the normal colon and following some type of acute sensitisation); (4) evaluate if the compound has visceroanalgesic properties on …

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