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ABSTRACT: 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. 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 mRNA were measured in tissues from mice using quantitative reverse transcription PCR and in situ hybridization. We used human intestinal cell lines to measure release of cGMP by linaclotide. We performed a post-hoc analysis of data from a Phase 3, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290μg linaclotide, once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. 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, were found to express linaclotide's target, GC-C. The downstream effector of GC-C, cyclic-guanosine- 3',5'-monophosphate (cGMP), was released following 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. Over 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%). 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.
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ABSTRACT: Neuropeptide W (NPW) is an endogenous ligand for the receptors GPR7 and GPR8 and is involved in central regulation of energy homeostasis. NPW in the periphery is found in gastric gastrin (G)-cells. In the stomach, energy intake is influenced by vagal afferent signals so we aimed to determine the effect of NPW on mechanosensitive gastric vagal afferents under different feeding conditions. Female C57BL/6 mice (N >10/group) were fed a standard laboratory diet (SLD), high fat diet (HFD), or were food restricted. The relationship between NPW immunopositive cells and gastric vagal afferent endings was determined by anterograde tracing and NPW immunohistochemistry. An in vitro gastro-oesophageal preparation was used to determine the functional effects of NPW on gastric vagal afferents. Expression of NPW in the gastric mucosa and GPR7 in whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). The expression of GPR7 in gastric vagal afferent neurons was determined by retrograde tracing and QRT-PCR. NPW immunoreactive cells were found in close proximity to traced vagal afferents. NPW selectively inhibited responses of gastric vagal tension receptors to stretch in SLD but not HFD or fasted mice. In the nodose ganglia, GPR7 mRNA was specifically expressed in gastric vagal afferent neurons. In fasted mice gastric mucosal NPW and nodose GPR7 mRNA was reduced compared to SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. NPW modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status. This article is protected by copyright. All rights reserved.
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