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Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics. Linaclotide and plecanatide are synthetic peptide agonists of guanylate cyclase-C (GC-C), a transmembrane receptor that is predominantly located on intestinal epithelial cells. These medications have very low oral bioavailability, which, when combined with the expression profile of GC-C, provides a mechanism of action 'targeted to the gut'. Linaclotide has been shown to inhibit colonic nociceptors and reduce peripheral drive from the colon, resulting in reduced numbers of activated dorsal horn neurons within the spinal cord and reduced pain responses to noxious colorectal distension. These effects are greatest in animal models of chronic visceral hypersensitivity that drive the 'bottom-up' and/or 'top-down' sensitization relevant to irritable bowel syndrome (IBS). Activation of GC-C results in the generation and release of cyclic guanosine-3′,5′-monophosphate (cGMP) from intestinal epithelial cells. When released into the submucosal space through the basolateral membrane, extracellular cGMP acts as a neuromodulator to inhibit pain-sensing nerve fibers innervating the colon. cGMP has also been demonstrated to inhibit pain-sensing nerves from human donors. In all human Phase III clinical studies conducted to date in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC), linaclotide significantly improved abdominal pain, discomfort, and bloating. Recent preclinical studies also provide the prospect that linaclotide may offer a novel therapeutic option, not only for the treatment of chronic abdominal pain in IBS-C, but also comorbid bladder dysfunction and endometriosis-associated pain. [ABSTRACT FROM AUTHOR]

Guanylate cyclase-C (GC-C) is a transmembrane receptor activated by bacterial heat-stable enterotoxins and by the endogenous hormones guanylin and uroguanylin. GC-C plays key roles in the regulation of intestinal fluid and electrolyte homeostasis. This is highlighted by several recently identified human mutations in GUCY2C, the gene encoding GC-C, which leads to the respective gain or loss of function of GC-C, resulting in profound effects on gastrointestinal function. However, a wealth of recent studies indicates GC-C signalling extends to a multitude of diverse additional functions. Recent pre-clinical and clinical studies demonstrate a novel first-in-class GC-C activating peptide, Linaclotide, provides effective relief from constipation and abdominal pain in patients with chronic constipation and constipation-predominant Irritable Bowel Syndrome. Accumulating evidence also suggests GC-C plays protective roles in mucosal barrier function, tissue injury and inflammation, whilst GC-C signalling is a key regulator of intestinal cell proliferation and apoptosis. Finally, recently identified extra-intestinal GC-C signalling pathways make novel contributions to the regulation of food intake and symptoms associated with Attention Deficit Hyperactivity Disorder. Consequently, these findings provide GC-C expression and its associated mutations as potential diagnostic markers for disease. They also provide current and future therapeutic potential for GC-C signalling within and outside the gastrointestinal tract. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The extract from the stem bark of Garcinia buchananii trees is used as an anti-diarrhea remedy in sub-Saharan Africa. We tested the hypothesis that G. buchananii bark extract and its anti-motility fractions are effective treatments against lactose-induced diarrhea. Materials and methods: A high-lactose (35%) diet was used to induce diarrhea in Wistar rats, which were then treated with either G. buchananii bark extract (0.1, 0.5, 1.0 and 5.0g bark powder), and its anti-motility fractions isolated using preparative thin layer chromatography; termed PTLC1 (15mg) and PTLC5 (3.8mg) or loperamide (8.4mg). Drug preparations were dissolved in 1L except PTCL1 and PTLC5 that were dissolved in 100mL tap water. Numerous parameters were measured in each condition including consistency, fluid and mucus content of feces, body weight, water and food consumption, urine production and bloating. Results: Diarrheic rats produced watery or loose, mucuoid, sticky, feces. Fluids constituted 86% of stool mass compared with only 42% for control rats fed standard chow. Compared with controls, diarrheic rats produced more urine, lost weight and had bloated ceca and colons. All doses of the extract, its anti-motility fractions and loperamide individually stopped diarrhea within 6–24h of administration, whilst significantly reducing mucus and fecal fluid content, urine production and intestinal bloating. Rats treated with 0.1g extract, PTLC1 and PTLC5 gained weight, whilst PTLC5 also increased water intake. Conclusions: Garcinia buchananii extract and its anti-motility fractions are effective remedies against lactose-induced diarrhea. The extract contains compounds that reverse weight loss, promote food and water intake, supporting the notion that characterization of the compounds could lead to new therapies against diarrheal diseases. [Copyright &y& Elsevier]

Altered motility, discomfort and pain are common debilitating symptoms of patients with functional gastrointestinal disorders. However, these conditions represent a significant and unmet need for mainstream medical treatment, particularly after high profile therapeutic drug withdrawals due to safety concerns. As such an increasing number of sufferers are turning to alternative medicines in an effort to seek relief from their symptoms. Alternative medicines have traditionally been looked at by mainstream medicine with cynicism. However, new evidence demonstrates that the active components in natural products have actions on specific ion channels and receptors, many of which are located in sensory systems distributed throughout the body. These findings may not only explain the symptomatic benefit of these alternative medicines but also provide novel therapeutic targets for mainstream drug development. As such natural products represent a wealth of untapped potential which is waiting to be unlocked. [Copyright &y& Elsevier]

Abstract: An organism''s ability to perceive mechanical stimuli is vital in determining how it responds to environmental challenges. External mechanosensation is responsible for the senses of touch, hearing, proprioception and aspects of somatic pain. Internally, mechanosensation underlies the initiation of autonomic reflex control and all manner of visceral sensations including chronic pain. Despite our increased knowledge of the molecular identity of invertebrate proteins that convert mechanical stimuli into electrical signals, understanding the complete molecular basis of mammalian mechanotransduction is currently a major challenge. Although the number of candidate molecules that serve as mechanotransducers is ever increasing, debate currently rages as to whether or not they contribute directly or indirectly to mammalian mechanotransduction. Despite these controversies novel molecules have been identified and their contribution to mechanosensation, be it direct or indirect, have improved our understanding of the mechanisms underlying visceral mechanosensation. Moreover, they have provided potential new pharmacological strategies for the control of visceral pain. [Copyright &y& Elsevier]

Background & Aims: Although there are many candidates as molecular mechanotransducers, so far there has been no evidence for molecular specialization of visceral afferents. Here, we show that colonic afferents express a specific molecular transducer that underlies their specialized mechanosensory function: the transient receptor potential channel, vanilloid 4 (TRPV4). Methods: We found TRPV4 mRNA is highly enriched in colonic sensory neurons compared with other visceral and somatic sensory neurons. TRPV4 protein was found in colonic nerve fibers from patients with inflammatory bowel disease, and it colocalized in a subset of fibers with the sensory neuropeptide CGRP in mice. We characterized the responses of 8 subtypes of vagal, splanchnic, and pelvic mechanoreceptors. Results: Mechanosensory responses of colonic serosal and mesenteric afferents were enhanced by a TRPV4 agonist and dramatically reduced by targeted deletion of TRPV4 or by a TRP antagonist. Other subtypes of vagal and pelvic afferents, by contrast, were unaffected by these interventions. The behavioral responses to noxious colonic distention were also substantially reduced in mice lacking TRPV4. Conclusions: These data indicate that TRPV4 contributes to mechanically evoked visceral pain, with relevance to human disease. In view of its distribution in favor of specific populations of visceral afferents, we propose that TRPV4 may present a selective novel target for the reduction of visceral pain, which is an important opportunity in the absence of current treatments. [Copyright &y& Elsevier]

The trefoil factor family of peptides (TFF1, TFF2, TFF3) with their lectin activities play important roles in mucosal protection and repair. However, major gaps in understanding their molecular function have hampered therapeutic development for gastrointestinal disorders. We provide here a critical overview of the status quo. [ABSTRACT FROM AUTHOR]

Background & Aims: Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. Methods: We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3′,5′-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 μg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. Results: In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c −/− mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). Conclusions: We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C. [Copyright &y& Elsevier]

Background & Aims: The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRP ankyrin 1 (TRPA1) is implicated in inflammatory pain; it interacts with G-protein-coupled receptors, but little is known about its role in the gastrointestinal (GI) tract. Sensory information from the GI tract is conducted via 5 afferent subtypes along 3 pathways. Methods: Nodose and dorsal root ganglia whose neurons innnervate 3 different regions of the GI tract were analyzed from wild-type and TRPA1−/− mice using quantitative reverse-transcription polymerase chain reaction, retrograde labeling, and in situ hybridization. Distal colon sections were analyzed by immunohistochemistry. In vitro electrophysiology and pharmacology studies were performed, and colorectal distension and visceromotor responses were measured. Colitis was induced by administration of trinitrobenzene sulphonic acid. Results: TRPA1 is required for normal mechano- and chemosensory function in specific subsets of vagal, splanchnic, and pelvic afferents. The behavioral responses to noxious colonic distension were substantially reduced in TRPA1−/− mice. TRPA1 agonists caused mechanical hypersensitivity, which increased in mice with colitis. Colonic afferents were activated by bradykinin and capsaicin, which mimic effects of tissue damage; wild-type and TRPA1−/− mice had similar direct responses to these 2 stimuli. After activation by bradykinin, wild-type afferents had increased mechanosensitivity, whereas, after capsaicin exposure, mechanosensitivity was reduced: these changes were absent in TRPA1−/− mice. No interaction between protease-activated receptor-2 and TRPA1 was evident. Conclusions: These findings demonstrate a previously unrecognized role for TRPA1 in normal and inflamed mechanosensory function and nociception within the viscera. [Copyright &y& Elsevier]

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition. [ABSTRACT FROM AUTHOR]