Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities

Abstract

Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.

Keywords: animal models; colorectal distension; irritable-bowel syndrome; microbiota–gut–brain axis; psychological; stress; visceral pain.

Figure 1

Spinal innervation of the gastrointestinal tract. The upper GI tract (including esophagus and stomach) is innervated with thoracic and lumbar afferents. The mid GI tract composed of the small intestine is innervated by both thoracic and lumbar afferents. The mid to lower GI tract including the large intestine is innervated by lower lumbar afferents and upper sacral afferents. The pelvic region is innervated by sacral afferents.

Figure 2

Ascending and descending pathways mediating visceral pain sensation. The ascending pathway for visceral pain perception from the periphery through the dorsal root ganglia via the dorsal reticular nucleus to the primary somatosensory cortex, insula, pregenual anterior cingulate cortex (pACC), and the midcingulate cortex (MCC). The descending pathway is mediated via signals from the ACC, thalamus, and amygdala to the periaqueductal gray (PAG), locus coeruleus, and raphe nucleus, returning via the rostral ventral medulla to the colon.

Figure 3

Routes of communication along the microbiota– brain–gut axis. Several pathways have been proposed to understand the communication between the intestinal microbiota and brain function, some of which have been summarized in this figure. These include neuroendocrine (hypothalamic–pituitary–adrenal axis), immune system (neuromodulating cytokines), enteric nervous system, autonomic nervous systems (vagus nerve), and spinal afferents. 5-hydroxytryptamine (5-HT) is produced by enterochromaffin cells in the GI tract. Gut microbes produce tryptophan-related metabolites, gut hormones, short chain fatty acids (SCFAs), and neurometabolites GABA, noradrenaline, and dopamine potentially modulating CNS function. Stress can influence the microbial composition of the intestine through the release of stress hormones (corticosterone/cortisol) or sympathetic neurotransmitters that in turn can influence gut physiology and alter the microflora balance. DC, dendritic cell; EC, enteroendocrine cells; ECC, enterochromaffin cells.

Figure 4

Schematic of the localization of toll-like receptors (TLRs). TLRs are located on the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6, TLR10) with the exception of TLR3, TLR7, TLR8, and TLR9, which are localized in the endosomal compartment.

Figure 5

Schematic representation of both physical and psychological stressors used in the generation of animal models for stress-induced visceral hypersensitivity. WAS, water-avoidance stress; PRS, partial restraint stress; TNBS, trinitro benzene sulfonic acid; DSS, dextran sodium sulfate.

Figure 6

Maternal separation model of brain–gut axis dysfunction. Adult rodents subjected to maternal separation in early life develop the characteristic MS phenotype; typified by altered; visceral sensation, microbiota, immune response, anxiety, depression, intestinal permeability, stress response, neurochemistry adapted from Ref. (108).