Some of the challenges in drug development for irritable bowel syndrome.

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! ), identification of drugs which can normalise this enhanced perception should be a major eVort in the search for eVective IBS medications. Enhanced perception of diVerent 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. Any 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 aVerents as well as dorsal horn neurones thereby resulting in acute visceral hyperalgesia, 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. The strategies pursued by optimists in this field are variations of the following sequence: (1) identify receptors or ion channels on visceral aVerent 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 unit activity of single aVerent nerve fibres; and (5) take the compound into clinical testing. (The pessimists would say IBS is a psychosomatic disease which is not amenable to pharmacological treatment and results obtained from studies in rats cannot be extrapolated to humans.) For example, an approach as outlined above has been taken for kappa opioid agonists and 5-HT3 receptor antagonists. 8 Based on such studies, both compounds have been proposed as peripherally acting visceral analgesics which can relieve visceral hypersensitivity in IBS. Even though such a view may be attractive from a marketing standpoint, it may not be the whole story. Ironically, the first of these compounds demonstrated impressive visceroanalgesic and antihyperalgesic eVects in the rat and in one study in humans, but was ineVective in relieving IBS symptoms. For the 5-HT3 receptor antagonist it was the other way around: visceroanalgesic properties of the compound in the true sense of the word were never demonstrated in the human colon, even though it was highly eVective in relieving key IBS symptoms. All too often it is ignored that candidate compounds have peripheral and central eVects, which may be important to explain their beneficial eVects in treating IBS patients. A good example to illustrate this point are the opioids: mu opioid receptors are present on multiple peripheral and central neurones, including vagal and spinal aVerents, on neurones in the superficial dorsal horn, medulla, locus coeruleus, amygdala, and anterior cingulate cortex. Following peripheral administration of a mu opioid receptor agonist, analgesia and antihyperalgesia result from the integrated eVect of the compound on pain transmission, pain modulation, and modulation of attentional, emotional, and autonomic mechanisms. The non-specific somatostatin receptor (SSTR) octreotide has also gone through some of the steps outlined above. Even though there is some anecdotal evidence and theoretical reasons to suggest that this compound (or more specific SSTR agonists) may be beneficial in the treatment of visceral pain, the mechanism(s) by which SSTR agonists might relieve clinical manifestations of IBS symptoms is not known. Based on preclinical and clinical studies, diVerent laboratories have postulated a peripheral or spinal 17 mechanism of action. In this issue of Gut, Su and colleagues present convincing evidence that in the rat, octreotide, a non-selective SSTR agonist which interacts with the SST receptor subtypes 2, 3, and 5, does not aVect pelvic nerve activation by colorectal distension, regardless of whether the colon is in a physiological or acutely inflamed state (see page 676). In contrast, and in agreement with several other preclinical and clinical studies, intrathecal administration of the compound has clear analgesic properties. Readers of this article, including investigators in the pharmaceutical industry who have selective SSTR agonists on their shelves and who are more than eager to develop an eVective IBS drug, might ask two questions: do these results allow us to conclude that when octreotide was given to humans, the eVect was also mediated by SSTRs in the spinal cord and not on aVerent nerve terminals in the gut, or on supraspinal sites, such as the anterior cingulate cortex or the locus coeruleus? Do these studies provide any evidence to suggest that SSTR agonists may be useful in the treatment of IBS symptoms? Any