Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments

Abstract

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

Keywords: Abdominal Pain; Histamine; Inflammation; Inflammatory Bowel Disease; Irritable Bowel Syndrome; Microbiome; Serotonin; Visceral Pain.

Figure 1 -. Chronic visceral pain is a disorder of the gut brain axis.

Nociceptors have cell bodies that lie in the dorsal root ganglia (DRG) and pseudounipolar axons that connect the intestine and the spinal cord. These synapse with second order neurons in the spinal cord and, thereafter, with central ascending pathways. Nociceptive neurotransmission in the spinal cord is modulated by descending pathways. At the level of the mucosa, nociceptive terminals are both mechanosensitive and chemosensitive, and are stimulated by luminal factors (e.g., microbial products, nutrients), as well as by host mediators released due to infection, inflammation, or tissue damage (e.g., serotonin, histamine, proteases, chemokines, and cytokines). These mediators can act indirectly via the epithelium/enterochromaffin cells or can stimulate nociceptors directly if there is a breakdown in the mucosal barrier. This results in sensitization of ion channels such as TRP, resulting in increased visceral pain.

Figure 2.. Mechanisms underlying gut microbiome driven visceral nociception.

Gut microbiome-derived products can sensitize peripheral nociceptors directly or act indirectly by stimulating immune cells and/or enterochromaffin cells to release cytokines, chemokine,s and/or serotonin respectively. The gut microbiome can also modulate intestinal barrier function by altering the luminal bile acid and protease pool or through metabolites such as butyrate.

Figure 3 -. Novel mechanisms causing increased histamine signaling to intestinal nociceptors.

Left schema shows that following combined food antigen (red triangle) and acute self-limiting colitis or combined food antigen and psychological stress exposure, re-exposure to food antigen alone triggers increased IgE release within the intestine (which is not systemic) causing mast cell degranulation within the intestinal wall. The ensuing histamine release causes nociceptor sensitization and increased pain signaling. Right schema shows that ingestion of poorly absorbed complex carbohydrates (CHO)s, (e.g., FODMAPs) can stimulate microbial production of histamine. Patients with Klebsiella aerogenes produce up to 100-times more histamine than those lacking this bacterium in their stool samples. Luminal histamine stimulates H₄ and H₁ receptors, leading to mast cell degranulation with ensuing nociceptor sensitization and increased pain signaling.

Figure 4 –. Areas for future investigation in peripheral mechanisms of visceral pain.

There is a need to identify peripheral mechanisms underlying visceral pain and develop novel therapeutic agents to treat patients. Identification of microbial vs. host sources of peripheral targets (e.g., GABA, endocannabinoids, 5HT), is one such mechanistic area. Evaluation of the relative contribution of each pathophysiologic mechanism to nociceptor sensitization in individual patients, and thus use of combination therapies targeting these mechanisms, is key. For opiates, some promising strategies for the development of safe yet effective opiate therapies are the development of pH-sensitive opiate analogues active at the site of inflammation, use of peripherally restricted agents or subthreshold combinations of opiates and cannabinoid-1 (CB1) receptor agonists. As chronic visceral pain is more common in women, future studies should evaluate whether pain mechanisms are sex-specific, and whether treatments should be utilized in a sex-specific manner.