Peripheral kappa‐opioid agonists for visceral pain

Kappa ( κ )‐ opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located κ ‐receptors and possibly, at least for some nonpeptidic κ ‐agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmennorhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first κ ‐agonists to be developed were brain‐penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to κ ‐receptors located behind the blood–brain barrier. New drug discovery programs are now geared towards the design of peripherally‐selective κ ‐agonists. So far, most of the organic molecule‐based peripheral κ ‐agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of κ ‐agonists in visceral pain. Additional clinical studies with safer κ ‐agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide‐based κ ‐agonists, which have shown unprecedented levels of peripheral selectivity.British Journal of Pharmacology (2004) 141 , 1331–1334. doi: 10.1038/sj.bjp.0705763