Emerging therapeutic approaches for treating abdominal pain.

There is an urgent need for analgesics to treat pain that lacks the serious side effects of existing drugs, such as conventional opioids and nonsteroidal anti-inflammatory drugs. Most side effects arise from the non-selective actions of these drugs at sites where the pain is not generated because of the ubiquitous expression of the drug targets in the body regardless of the underlying disease. In this narrative review, we explore 2 mechanistic approaches focusing on visceral nociceptive neurons that have the potential to limit side effects while preserving efficacy. Strategy 1 demonstrates how mechanistic pain studies underlying a specific disorder, such as irritable bowel syndrome, can identify targets specifically upregulated in that condition. We discuss recent findings regarding 2 neuroactive mediators, histamine and proteases, including novel intestinal sources, signalling pathways, and intracellular synergistic actions that could serve as potential therapeutic targets. Strategy 2 examines how acidic microenvironments unique to the sites of inflammation where pain is generated, such as in inflammatory bowel disease, can be exploited. pH-sensitive analgesics have been developed that inhibit μ-opioid receptors at sites of inflammation where tissue pH is low, ie, 6.5, while showing no activity at other sites where tissue pH is normal, ie, 7.4. Collectively, these studies highlight the value of investigating the mechanisms underlying specific disorders, which can lead to novel biomarkers and therapeutic strategies that can enhance the specificity of the new therapies.