Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD.

Introduction: The world population is ageing, resulting in increased prevalence of age-related comorbidities and healthcare costs. Limited data are available on intestinal health in elderly populations. Structural and functional changes, including altered visceroperception, may lead to altered bowel habits and abdominal symptoms in healthy individuals and irritable bowel syndrome (IBS) patients. Our aim was to explore age-related changes in gastrointestinal symptoms and underlying mechanisms.Methods: In total, 780 subjects (IBS patients n = 463, healthy subjects n = 317) from two separate studies were included. Subjects were divided into different age groups ranging from young adult to elderly. Demographics and gastrointestinal symptom scores were collected from all participants using validated questionnaires. A subset of 233 IBS patients and 103 controls underwent a rectal barostat procedure to assess visceral hypersensitivity. Sigmoid biopsies were obtained from 10 healthy young adults and 10 healthy elderly. Expression of the visceral pain-associated receptors transient receptor potential (TRP) Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) genes were investigated by quantitative RT-PCR and immunofluorescence.Results: Both elderly IBS and healthy individuals showed significantly lower scores for abdominal pain (p < 0.001) and indigestion (p < 0.05) as compared to respective young adults. Visceral hypersensitivity was less common in elderly than young IBS patients (p < 0.001). Relative TRPA1 gene transcription, as well as TRPA1 and TRPV1 immunoreactivity were significantly lower in healthy elderly versus healthy young adults (p < 0.05).Conclusions: Our findings show an age-related decrease in abdominal pain perception. This may in part be related to decreased TRPA1 and/or TRPV1 receptor expression. Further studies are needed to reveal precise underlying mechanisms and the associations with intestinal health.

Neuroimaging studies have revealed important pathomechanisms related to disorders of brain–gut interactions, such as irritable bowel syndrome and functional dyspepsia. More detailed investigations aimed at neural processing in the brainstem, including the key relay station of the nucleus of the solitary tract (NTS), have hitherto been hampered by technical shortcomings. To ascertain these processes in more detail, we used multiecho multiband 7T functional magnetic resonance imaging and a novel translational experimental model based on a nutrient-derived intestinal chemonociceptive stimulus. In a randomized cross-over fashion, subjects received duodenal infusion of capsaicin (the pungent principle in red peppers) and placebo (saline). During infusion, functional magnetic resonance imaging data and concomitant symptom ratings were acquired. Of 26 healthy female volunteers included, 18 were included in the final analysis. Significantly increased brain activation over time during capsaicin infusion, as compared with placebo, was observed in brain regions implicated in pain processing, in particular the NTS. Brain activation in the thalamus, cingulate cortex, and insula was more pronounced in subjects who reported abdominal pain (visual analogue scale > 10 mm), as compared with subjects who experienced no pain. On the contrary, activations at the level of the NTS were independent of subjective pain ratings. The current experimental paradigm therefore allowed us to demonstrate activation of the principal relay station for visceral afferents in the brainstem, the NTS, which was engaged irrespective of the conscious pain response. These findings contribute to understanding the fundamental mechanism necessary for developing novel therapies aimed at correcting disturbances in visceral afferent pain processing.

Low dose tricyclic antidepressants may be effective for patients with functional dyspepsia (FD), although high-quality randomized controlled trials (RCTs) are limited. We aimed to investigate the efficacy of nortriptyline in an escalating low dose regimen vs placebo in participants with FD following a genotype-guided pre-selection based on cytochrome P450 2D6 (CYP2D6), the primary enzyme responsible for nortriptyline metabolism. We conducted a multicenter, RCT of patients with FD in primary, secondary and tertiary care. 69 participants were randomly assigned to nortriptyline (week 1-2: 10mg; week 3-4: 25mg; week 5-12: 50mg) versus placebo for a 12-week treatment. The primary outcome was clinical response based on a decrease in FD symptoms of at least 30% compared to baseline, in 50% of the last 10 weeks of the treatment period. The primary outcome showed no significant difference in response for nortriptyline compared to placebo (45% vs 58%; OR, 0.574; 95% CI, 0.211 to 1.560; p=0.276). There was no significant difference in adverse events between the nortriptyline and placebo group. Nortriptyline plasma levels were significantly higher in responders compared to non-responders (13.0 μg/L; IQR, 12.0-16.0 vs 9.0 μg/L; IQR, 8.0-10.5; p=0.003). The belief to have received nortriptyline showed a higher response rate than the belief to have received placebo (77% vs 36%; OR, 11.439; 95% CI, 2.138 to 61.201; p=0.004). Nortriptyline was not more effective than placebo in reducing FD symptoms in participants pre-selected based on CYP2D6 genotype, although a biological effect of nortriptyline could not be ruled out. However, effects related to participants' belief appeared to be stronger; Clinicaltrials.gov number, NCT03652571.