Critical evaluation of animal models of visceral pain for therapeutics development: A focus on irritable bowel syndrome

Abstract

The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut‐brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain

“…These functional afferent subtypes correspond with seven different molecular subtypes of afferents [74]. Afferent sensitivity can also be profoundly affected by interactions with the mucosal epithelium, motility patterns [75][76][77][78][79], and by 'bottom-up' and 'top-down' sensitization [32,33]. Overall, these data suggest that the ascending pathways may diverge according to the nature and region of the stimulus [60].…”

“…Generally speaking, spinal afferents are responsible for signaling nociceptive stimuli, particularly from the colorectum [30,31] (for details see Box 3). Visceral hypersensitivity, in particular the enhanced responses of colonic afferents to mechanical and/or chemical stimuli, is implicated in the development and maintenance of visceral pain in IBS [31][32][33].…”

Changes in fecal short‐chain fatty acids following fecal microbiota transplantation in patients with irritable bowel syndrome

“…The role of the increased levels of isobutyric, isovaleric, and valeric acids in the 60‐g group after FMT is not clear. Further studies using animal models may shed light on the pathophysiology of SCFAs in IBS 29 …”

Review article: current and future treatment approaches for pain in IBS

“…At the pre-clinical level, a number of animal models 103 and novel neuroimmune 104 and nervous system 105 targets have been flagged up for IBS pain. Resolvin agonists (endogenous anti-inflammatory lipid mediators with somatic analgesic properties via transient receptor potential V1 modulation) have shown some promise in pre-clinical IBS pain models.…”