GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation

Although an extensive body of literature confirmed γ-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut …

Novel evidences for a role of dopamine as modulator of intestinal motility: a study on mouse distal colon

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. It has been classically considered that the pathological hallmarks of PD affect primarily the substantia nigra. Nevertheless, it has become increasingly evident that PD is a multicentric neurodegenerative process that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system (ENS). Pathological alterations within the ENS could be involved in the gastrointestinal (GI) dysfunction frequently encountered by PD patients. Dopamine (DA) seems to be a major candidate for the impairment of GI function in PD since its levels were found to be decrea…

Arginine vasopressin, via activation of post-junctional V1 receptors, induces contractile effects in mouse distal colon

The aim of this study was to analyze whether arginine vasopressin (AVP) may be considered a modulator of intestinal motility. In this view, we evaluated, in vitro, the effects induced by exogenous administration of AVP on the contractility of mouse distal colon, the subtype(s) of receptor(s) activated and the action mechanism. Isometric recordings were performed on longitudinal and circular muscle strips of mouse distal colon. AVP (0.001 nM-100 nM) caused concentration-dependent contractile effects only on the longitudinal muscle, antagonized by the V1 receptor antagonist, V-1880. AVP-induced effect was not modified by tetrodotoxin, atropine and indomethacin. Contractile response to AVP was…

Postnatal development of the dopaminergic signaling involved in the modulation of intestinal motility in mice

Background:Since antidopaminergic drugs are pharmacological agents employed in the management of gastrointestinal motor disorders at all ages, we investigated whether the enteric dopaminergic system may undergo developmental changes after birth.Methods:Intestinal mechanical activity was examined in vitro as changes in isometric tension.Results:In 2-d-old (P2) mice, dopamine induced a contractile effect, decreasing in intensity with age, replaced, at the weaning (day 20), by a relaxant response. Both responses were tetrodotoxin (TTX)-insensitive. In P2, dopaminergic contraction was inhibited by D1-like receptor antagonist and mimicked by D1-like receptor agonist. In 90-d-old (P90) mice, the …

"In medio stat virtus": Concentration-dependent effects of GABA on colonic motor patterns in mice

BACKGROUND AND AIMS: In the enteric nervous system, GABA (gamma amino butyric acid) has been shown to modulate neuronal activity via activation of different GABAergic receptors. The consequences of this modulation remain poorly understood and depend on the region of the gastrointestinal (GI) tract or on the animal species examined. Although several studies have been addressed the role of GABA as neuromodulator in the upper part of GI tract, accumulating data suggest that it may play a key role also in GI distal tract function in health and disease. Therefore, the aim of this study was to investigate the role of GABA in both spontaneous and electrically-evoked contractions and in the perista…

Opposite role played by GABAA and GABAB receptors in the modulation of peristaltic activity in mouse distal colon.

We investigated the role of GABA on intestinal motility using as model the murine distal colon. Effects induced by GABA receptors recruitment were examined in whole colonic segments and isolated circular muscle preparations to analyze their influence on peristaltic reflex and on spontaneous and neurally-evoked contractions. Using a modified Trendelenburg set-up, rhythmic peristaltic contractions were evoked by gradual distension of the colonic segments. Spontaneous and neurally-evoked mechanical activity of circular muscle strips were recorded in vitro as changes in isometric tension. GABA, at low concentrations (10-50 µM), potentiated peristaltic activity and the neural cholinergic contrac…

Angiotensin II type II receptors and colonic dysmotility in 2,4-dinitrofluorobenzenesulfonic acid-induced colitis in rats

Background: Angiotensin II (Ang II), the main peptide of the renin-angiotensin system (RAS), has been suggested to be involved in inflammatory bowel diseases. Since RAS has emerged as gut motility regulator, and dysmotility is associated with intestinal inflammation, our objective was to investigate in rat 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis the functionality of RAS and its contribution to colonic motor alterations. Methods: The effects of Ang II on the longitudinal colonic muscular contractility of control and DNBS-treated rats were characterized in vitro. Transcripts encoding for Ang II receptors were investigated by RT-PCR. Key Results: Inflamed preparations showed a l…

Activation of angiotensin II type 1 receptors and contractile activity in human sigmoid colon in vitro.

We propose and validate a non-invasive method that enables accurate detection of the discharge times of a relatively large number of motor units during excitatory and inhibitory reflex stimulations. HDsEMG and intramuscular EMG (iEMG) were recorded from the tibialis anterior muscle during ankle dorsiflexions performed at 5%, 10%, and 20% of the maximum voluntary contraction (MVC) force, in 9 healthy subjects. The tibial nerve (inhibitory reflex) and the peroneal nerve (excitatory reflex) were stimulated with constant current stimuli. In total, 416 motor units were identified from the automatic decomposition of the HDsEMG. The iEMG was decomposed using a state-of-the-art decomposition tool a…

GABA & “LITTLE BRAIN”: RUOLO EMERGENTE NEL CONTROLLO DELLA MOTILITÀ INTESTINALE

L’acido gamma-ammino butirrico (GABA) è ampiamente riconosciuto come principale neurotrasmettitore inibitore nel sistema nervoso centrale dei mammiferi. Tuttavia numerose evidenze sperimentali suggeriscono una sua azione anche a livello del sistema nervoso enterico (o “little brain”), sezione del sistema nervoso periferico deputata al controllo della funzionalità del tratto gastrointestinale (GI). Dal momento che, ad oggi, gli effetti del GABA rimangono ancora non chiari e sembrerebbero dipendere dalla porzione del tratto GI considerata o dal modello animale esaminato, lo scopo di questo lavoro è stato quello di studiare l’effetto del GABA sulla contrattilità della muscolatura circolare del…

Angiotensin II type-2 receptors and colonic dysmotility associated to experimental colitis in rats

Angiotensin II (Ang II) is a newly discovered modulator of intestinal motility, mainly via activation of excitatory AT1 receptors (AT1R). We demonstrated that during gut inflammation there is a recruitment of inhibitory AT2 receptors (AT2R) which would counteract the AT1R-induced effects. Our objective was to explore the consequence of AT2R activation in the pathogenesis of experimental colitis. Colitis was induced in rats by intrarectal administration of 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by macro- and microscopic scores, myeloperoxidase activity and inflammatory cytokine expression on day 6 after colitis induction. Colonic contractility was recorded in vi…

Role for D1-like and D2-like dopamine receptors in the modulation of intestinal motility in mice

Objective: In the last years a plethora of studies addressed dopamine (DA) as a modulator within the enteric nervous system (ENS), controlling gastrointestinal (GI) functions via activation of D1- and D2-like receptors. However, the effective role and functional significance of DA in the ENS, and the contribution of its receptors, are still a matter of debate. Pathological alterations of dopaminergic system in the gut may be likely implicated in different motor GI disorders, including dyspepsia and gastroparesis. Thus, a detailed characterization of the enteric dopaminergic signalling is necessary. The aim of this study was to explore the role of DA in the GI tract, using as model the mouse…

Opposite effects of dopamine on the mechanical activity of longitudinal and circular muscles in human colon

Objective: Dopamine (DA) has been proposed to act as a modulator of GI motility, via activation of specific receptors D1- and D2-like receptors widely expressed throughout the length of the gastrointestinal tract, in different animal species. However, little and not clear information are available about DA effect in the human gut. The aims of this study were to elucidate whether dopamine may affect contractility in human colon, the receptor subtypes involved and the possible differences in the function and distribution of dopaminergic receptors between longitudinal and circular muscle. Methods: Mechanical responses to dopamine were examined in vitro as changes in isometric tension in strips…

Dopamine induces inhibitory effects on the circular muscle contractility of mouse distal colon via D1- and D2-like receptors

Dopamine (DA) acts as gut motility modulator, via D1- and D2-like receptors, but its effective role is far from being clear. Since alterations of the dopaminergic system could lead to gastrointestinal dysfunctions, a characterization of the enteric dopaminergic system is mandatory. In this study, we investigated the role of DA and D1- and D2-like receptors in the contractility of the circular muscle of mouse distal colon by organ-bath technique. DA caused relaxation in carbachol-precontracted circular muscle strips, sensitive to domperidone, D2-like receptor antagonist, and mimicked by bromocriptine, D2-like receptor agonist. 7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz…

The GABAergic System and the Gastrointestinal Physiopathology.

Since the first report about the presence of γ-aminobutyric acid (GABA) within the gastrointestinal (GI) tract, accumulating evidence strongly supports the widespread representation of the GABAergic system in the enteric milieu, underlining its potential multifunctional role in the regulation of GI functions in health and disease. GABA and GABA receptors are widely distributed throughout the GI tract, constituting a complex network likely regulating the diverse GI behaviour patterns, cooperating with other major neurotransmitters and mediators for maintaining GI homeostasis in physiologic and pathologic conditions. GABA is involved in the circuitry of the enteric nervous system, controlling…

GABAergic System in Action: Connection to Gastrointestinal Stress-related Disorders.

Background: Currently, treatment of stress-related gastrointestinal disorders, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), is mainly symptomatic since there is no drug on the market that solves effectively diverse disease symptoms and comorbid states. Thus, recently GABA receptors have been identified within gastrointestinal system and it has been recognized that among various GABAergic drugs some of them influence gastrointestinal stress-related diseases. Firstly, benzodiazepines have been investigated due to their diverse effects: neuroimmunomodulatory, relief of visceral pain and anxiolytic action. Conclusion: The present review brings findings on the exp…

POSTNATAL MATURATION OF SEROTONIN SIGNALING SYSTEM IN MOUSE DUODENUM

BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in central nervous system (CNS) temporal differences occur in the maturation of different neurotransmitter systems (Goldman-Rakic & Brown, 1982, Ehrlich et al., 2013). Although significant advances have been made in understanding the modifications in CNS, only primarily descriptive studies about the changes taking place in enteric nervous system (ENS), main regulator of gastrointestinal (GI) functions, have been underway. As the other organ systems, digestive system is still developing and maturing after birth and thus it is possible to speculate that the changes in the chemical coding of ENS may o…

POSTNATAL DEVELOPMENT OF THE 5-HYDROXYTRYPTAMINE (5-HT) SIGNALING SYSTEM IN THE MOUSE

New actors in the gut :emerging players in motility and in inflammatory bowel diseae

Gastrointestinal motility is an integrated process generated and modulated by local and circulating hormones and neurotransmitters which act and interact directly and indirectly on muscle cells. A plethora of regulators have been identified, but this field is continuously in expansion. Among the new actors in gut accumulating evidence strongly supports a role of renin-angiotensin system (RAS) in the digestive tract cooperating with other major mediators for maintaining gastrointestinal homeostasis. Transcripts encoding RAS components were detected in gastrointestinal tract and the involvement of RAS in gut motility modulation is increasingly emerging. The available literature demonstrated t…

Differential recruitment of Angiotensin II receptors in the modulation of rat colonic contractile activity in experimental inflammation

Objective: Inflammatory Bowel Diseases (IBD), are severe gastrointestinal (GI) disorders, with unknown aetiology, characterized by a chronic intestinal inflammatory reaction, progressively affecting GI functions, as gut motility. During inflammatory events, modifications in the functionality of some enteric modulators could contribute to the pathological changes of GI motor patterns. Angiotensin II (Ang II), the main effector of the renin-angiotensin system (RAS), has been recently reported as novel regulator of GI motility, acting on the specific receptors (AT1R and AT2R) located on the gut wall. Since recent studies have pointed out an involvement of RAS system in GI inflammation, we expl…

The enteric nervous system: from motility to inflammation

ANALISI DEL RUOLO DI MEDIATORI ENTERICI NELLA FISIOPATOLOGIA DELLE MALATTIE INFIAMMATORIE CRONICHE INTESTINALI

Smooth muscle and neural dysfunction contribute to different phases of murine postoperative ileus.

Background Postoperative ileus (POI) is characterized by a transient inhibition of gastrointestinal (GI) motility after abdominal surgery mediated by the inflammation of the muscularis externa (ME). The aim of this study was to identify alterations in the enteric nervous system that may contribute to the pathogenesis of POI. Methods Gastrointestinal transit, contractility of isolated smooth muscle strips and inflammatory parameters were evaluated at different time points (1.5 h to 10 days) after intestinal manipulation (IM) in mice. Immune-labeling was used to visualize changes in myenteric neurons. Key Results Intestinal manipulation resulted in an immediate inhibition of GI transit recove…

ROLE OF RENIN-ANGIOTENSIN SYSTEM IN COLONIC DYSMOTILITY ASSOCIATED WITH BOWEL INFLAMMATION IN RATS

Dysregulation of different mediator systems could contribute to the gut dismotility in inflammatory bowel diseases (IBDs), chronic disorders characterized by an exasperated immune response disturbing gut functions. Among these, Angiotensin II (Ang II), the main peptide of renin-angiotensin system (RAS), can participate in inflammatory responses and RAS components are increased in IBD patients. Since RAS has emerged as gut motility regulator, our objectives was to investigate, in an IBD rat model, the RAS functionality and its eventual contribution to colonic dismotility. Experimental colitis was induced in rats by intracolonic administration of 2,4-dinitrobenzenesulfonic acid (DNBS). Drug e…

MATERNAL HIGH FAT DIET CONSUMPTION DURING PREGNANCY AND LACTATION: IMPACT ON INTESTINAL MORPHOLOGY AND FUNCTION IN PREWEANING OFFSPRING

Different evidence supports an important role for maternal obesity in the development of childhood obesity and subsequent adult disease. This study is addressed to investigate if and to which extend maternal high fat feeding would induce compensatory and adaptative responses in gut predisposing to the eventual development of paediatric obesity. Adult female mice were divided into two groups fed with i) high fat (HF) diet and ii) standard chow (SC)diet, during pregnancy and lactation. HF mothers showed a significant weight gain, higher levels of blood glucose and an abnormal glucose tolerance compared to SC mother, indicating the establishment of metabolic syndrome. Then, offspring subdivide…