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Background and Purpose Adenosine A2B receptors regulate several physiological enteric functions. However, their role in the pathophysiology of intestinal dysmotility associated with inflammation has not been elucidated. Hence, we investigated the expression of A2B receptors in rat colon and their role in the control of cholinergic motility in the presence of bowel inflammation. Experimental Approach Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS). Colonic A2B receptor expression and localization were examined by RT-PCR and immunofluorescence. The interaction between A2B receptors and adenosine deaminase was assayed by immunoprecipitation. The role of A2B receptors in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). Key Results A2B receptor mRNA was present in colon from both normal and DNBS-treated rats but levels were increased in the latter. A2B receptors were predominantly located in the neuromuscular layer, but, in the presence of colitis, were increased mainly in longitudinal muscle. Functionally, the A2B receptor antagonist MRS 1754 enhanced both electrically-evoked and carbachol-induced cholinergic contractions in normal LMPs, but was less effective in inflamed tissues. The A2B receptor agonist NECA decreased colonic cholinergic motility, with increased efficacy in inflamed LMP. Immunoprecipitation and functional tests revealed a link between A2B receptors and adenosine deaminase, which colocalize in the neuromuscular compartment. Conclusions and Implications Under normal conditions, endogenous adenosine modulates colonic motility via A2B receptors located in the neuromuscular compartment. In the presence of colitis, this inhibitory control is impaired due to a link between A2B receptors and adenosine deaminase, which catabolizes adenosine, thus preventing A2B receptor activation. [ABSTRACT FROM AUTHOR]

Background: The frequency and clinical features of drug-related taste and/or smell impairments are currently unclear.Objective: The aim of this study was to identify major drug classes associated with taste and smell alterations reported to the Italian spontaneous adverse drug reaction (ADR) reporting database.Methods: The association between drug and altered taste or smell was investigated by case/non-case methodology. The reporting odds ratio (ROR) was used as a measure of disproportionality. Cases were defined as patients with at least one ADR related to taste or smell impairments. The non-cases included all patients without any ADRs related to taste or smell alterations.Results: According to the selection criteria, 52 166 reports were included in the analysis. Overall, 182 cases of drug-related taste and/or smell dysfunctions were identified. Statistically significant unadjusted RORs were reported for macrolides (n = 31; 7.1; 95% CI 4.8, 10.5), terbinafine (the only drug reported within the group of antimycotics belonging to the Anatomical Therapeutic Chemical class D01AE) [n = 17; 76.4; 95% CI 44.0, 132.6], fluoroquinolones (n = 15; 1.7; 95% CI 1.0, 2.8) and protein kinase inhibitors (n = 10; 4.0; 95% CI 2.1, 7.7). When RORs were adjusted for sex and age category, the disproportion remained statistically significant for all of the previously mentioned drug classes.Conclusions: Taste and/or smell abnormalities are common, sometimes unexpected and often persistent complaints of patients during pharmacological treatments. Physicians should be aware of the impact of these ADRs on patients' quality of life. [ABSTRACT FROM AUTHOR]

Experimental evidence in animal models suggests that adenosine is involved in the regulation of digestive functions. This study examines the influence of adenosine on the contractile activity of human colon. Reverse transcription-polymerase chain reaction revealed A1 and A2a receptor expression in colonic neuromuscular layers. Circular muscle preparations were connected to isotonic transducers to determine the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 receptor antagonist), ZM 241385 (A2a receptor antagonist), CCPA (A1 receptor agonist) and 2-[(p-2-carboxyethyl)-phenethylamino]-5′- N-ethyl-carboxamide-adenosine (CGS 21680; A2a receptor agonist) on motor responses evoked by electrical stimulation or carbachol. Electrically evoked contractions were enhanced by DPCPX and ZM 241385, and reduced by CCPA and CGS 21680. Similar effects were observed when colonic preparations were incubated with guanethidine (noradrenergic blocker), L-732,138, GR-159897 and SB-218795 (NK receptor antagonists). However, in the presence of guanethidine, NK receptor antagonists and Nω-propyl-l-arginine (NPA; neuronal nitric oxide synthase inhibitor), the effects of DPCPX and CCPA were still evident, while those of ZM 241385 and CGS 21680 no longer occurred. Carbachol-induced contractions were unaffected by A2a receptor ligands, but they were enhanced or reduced by DPCPX and CCPA, respectively. When colonic preparations were incubated with guanethidine, NK antagonists and atropine, electrically induced relaxations were partly reduced by ZM 241385 or NPA, but unaffected by DPCPX. Dipyridamole or application of exogenous adenosine reduced electrically and carbachol-evoked contractions, whereas adenosine deaminase enhanced such motor responses. In conclusion, adenosine exerts an inhibitory control on human colonic motility. A1 receptors mediate direct modulating actions on smooth muscle, whereas A2a receptors operate through inhibitory nitrergic nerve pathways. [ABSTRACT FROM AUTHOR]

Background and purpose:Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK1). However, the role played by cholecystokinin 2 (CCK2) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK2 receptors on the contractile activity of human distal colon.Experimental approach:The effects of compounds acting on CCK2 receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation.Key results:Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK2 receptor antagonist; +57% at 0.01 μM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by Nω-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by Nω-nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 μM).Conclusions and implications:CCK2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK2 receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.British Journal of Pharmacology (2007) 151, 1246–1253; doi:10.1038/sj.bjp.0707339; published online 18 June 2007 [ABSTRACT FROM AUTHOR]

BACKGROUND: There is ongoing debate about the safety of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic/noradrenergic antidepressants when used during pregnancy. OBJECTIVE: This article reviews the available literature on the main safety concerns associated with the use of SSRIs and other serotonergic/noradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants) during pregnancy. METHODS: English-language reports of analytical and descriptive studies, including case reports, case series, and meta-analyses, were identified through searches of MEDLINE, EMBASE, and PsycINFO (1966-April 2009). The search terms were fluoxetine, paroxetine, sertraline, Citalopram, escitalopram, fluvoxamine, venlafaxine, mirtazapine, reboxetine, duloxetine, SSRI, SNRI, NaSSA, and NRI in association with depression, pregnancy, prenatal exposure, miscarriage, spontaneous abortion, malformation, in utero exposure, and neonatal complications. RESULTS: Paroxetine has been associated with significant risks of major malformation, particularly cardiac defects, when used during pregnancy. Significant associations between maternal exposure to SSRIs and both persistent pulmonary hypertension of the newborn and a self-limiting neonatal behavioral syndrome have been reported in a number of recent original studies and meta-analyses. Some studies have suggested a relationship between the use of SSRIs or other serotonergic/noradrenergic antidepressants and the occurrence of miscarriage, although these studies had methodologic limitations that affected the strength of the data. Evidence for a possible association between in utero exposure to SSRIs or other serotonergic/noradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-interval prolongation is currently weak. CONCLUSION: The available evidence suggests that SSRIs and other serotonergic/noradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed to these agents in utero. [ABSTRACT FROM AUTHOR]

Background : Growing evidence highlights the relevance of the microbiota-gut-brain axis in Alzheimer's disease (AD). AD patients display gut dysbiosis, altered intestinal barrier and enteric inflammation that, besides bowel symptoms, can contribute to brain pathology. In this context, the modulation of gut microbiota is emerging as a therapeutical option to halt or slow down central pathology. Herein, we examined the effects of Lactiplantibacillus plantarum HEAL9 in a spontaneous mouse model of AD. Methods : Senescence-accelerated mouse prone 8 (SAMP8) mice and control SAMR1 mice were treated orally with HEAL9 1 × 10 9 CFU per mouse per day or placebo for two months to evaluate the effects of the probiotic during the earliest stages of AD, before the development of brain pathology. Cognitive impairment, in vivo and in vitro colonic motility, astrocyte and microglia reactive response, brain and colonic amyloid-β 1-42 (Aβ 1-42 ) levels, and inflammasome components activation (NLRP3, ASC, caspase-1 and interleukin-1β) were assessed. In addition, gut barrier alterations [circulating lipopolysaccharide-binding protein (LBP) levels] and acidic mucus were evaluated. Results : HEAL9 administration significantly attenuated cognitive impairment and counteracted colonic dysmotility in SAMP8 mice. Moreover, HEAL9 decreased astrogliosis and microgliosis, Aβ 1-42 accumulation and inflammasome activation in colon and brain and normalized plasma LBP levels and colonic acidic mucus content. Conclusion : HEAL9 intake alleviated cognitive decline and normalized colonic motility in the prodromal phases of AD via the modulation of microbiota-gut-inflammasome-brain signalling. Thus, dietary supplementation with HEAL9 could be considered as a suitable therapeutical option for the treatment of AD and related intestinal symptoms in the early stages of the disease.

Aim: In the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs)., Methods: Wild-type C57BL/6J and NLRP3-KO ( -/- ) mice were fed with high-fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP- and NLRP3-positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation., Results: HFD mice showed increased body weight, altered IEB integrity, increased GFAP-positive glial cells, and NLRP3 inflammasome hyperactivation. HFD-NLRP3 -/- mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase-1/IL-1β signaling. Enteric glial-derived IL-1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL-1β receptor antagonist) and with conditioned medium derived from silenced-NLRP3 glial cells., Conclusion: HFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase-1/IL-1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)