Alterations in gastrointestinal motility and secretion underlie the constipating action of therapeutically administered opiates. The prototype opiate is morphine, which acts to delay gastric emptying and intestinal transit, to suppress intestinal secretion of water and electrolytes and to suppress transport of bile into the duodenum. The effects of opiates, synthetic opioids and endogenously released opioid peptides on these organ-level gastrointestinal functions reflect actions on electrical and synaptic behaviour of neurones in the enteric nervous system. Adverse effects and positive therapeutic effects of administration of opioid-receptor-blocking drugs on the digestive tract must be understood in the context of the neurophysiology of the enteric nervous system and mechanisms of neural control of gastrointestinal smooth muscle, secretory glands and blood-lymphatic vasculature. We review here the integrated systems of physiology and cellular neurobiology that are basic to understanding the actions of opioid agonists and antagonists in the digestive tract.

BACKGROUND & AIMS 5-hydroxytryptamine receptor (5-HT4R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT4 receptors are expressed in the colonic epithelium and that 5-HT4R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS Mucosal expression of the 5-HT4R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT4R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl− secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT4R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS Mucosal 5-HT4 receptors were present in the small and large intestines. In the distal colon, 5-HT4 receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT4Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl− secretion. Luminal administration of 5-HT4R agonists accelerated propulsive motility; a 5-HT4R antagonist blocked this effect. Bath application of 5-HT4R agonists did not affect motility. Oral or intracolonic administration of 5-HT4R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT4R antagonist. CONCLUSIONS Mucosal 5-HT4 receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT4R agonists. Colon-targeted, intraluminal delivery of 5-HT4R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

Background-Angiotensin II-induced hypertension is associated with NAD(P)H oxidase-dependent superoxide production in the vessel wall. Vascular superoxide level is also increased in deoxycorticosterone acetate (DOCA)-salt hypertension, which is associated with a markedly depressed plasma renin activity because of sodium retention. However, the mechanisms underlying superoxide production in low-renin hypertension are undefined. Methods and Results-This study investigated (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt hypertensive rats, contributes to arterial superoxide generation and (2) the effect of gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase. Both superoxide and ET-1 levels were significantly elevated in carotid arteries of DOCA-salt rats compared with that of the sham-operated controls. ET-1 concentration-dependently stimulated superoxide production in vitro in carotid arteries of normotensive rats. The increase in arterial superoxide in both ET-1-treated normotensive and DOCA-salt rats was reversed by a selective ET A receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor N -L-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET A receptors significantly reduced arterial superoxide levels, with a concomitant decrease of systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese superoxide dismutase or endothelial nitric oxide synthase also suppressed superoxide levels in carotid arteries of DOCA-salt rats. Conclusions-These findings suggest that ET-1 augments vascular superoxide production at least in part via an ET A /NADPH oxidase pathway in low-renin mineralocorticoid hypertension.

SummaryBackgroundThe nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs).AimTo perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy.MethodsArticles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.ResultsRetrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically.Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride).Conclusions5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility.

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A diamond microelectrode was used to sensitively, reproducibly and stably record overflow of 5-hydroxytryptamine (5-HT, serotonin) from enterochromaffin cells (EC) of the intenstinal mucosal layer. 5-HT is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. The diamond microelectrode was formed by overcoating a sharpened 76 microm diameter Pt wire with a thin layer of conducting diamond. After insulation with polypropylene, the conically-shaped microelectrode had a diameter of about 10 microm at the tip and 80 microm at the cylindrical portion. The exposed length was 100-200 microm. Continuous amperometry with the microelectrode poised at a detection potential of 700 mV vs. Ag|AgCl was used to measure 5-HT overflow as an oxidation current. 5-HT overflow was elicited by both mechanical and electrical stimulation. Some minor electrode fouling, a common problem with the oxidative detection of 5-HT, was seen for diamond but the response stabilized enabling recording in vitro. Both 5-HT and the paracrine hormone, melatonin, were detected in the extracellular solution. The 5-HT oxidation current increased in the presence of the serotonin transporter (SERT) inhibitor, fluoxetine (1 microM), providing evidence that the oxidation current was associated with 5-HT.

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Transmitter-gated cation channels are detectors of excitatory chemical signals at synapses in the nervous system. Here we show that structurally distinct alpha3beta4 nicotinic and P2X2 channels influence each other when co-activated. The activation of one channel type affects distinct kinetic and conductance states of the other, and co-activation results in non-additive responses owing to inhibition of both channel types. State-dependent inhibition of nicotinic channels is revealed most clearly with mutant P2X2 channels, and inhibition is decreased at lower densities of channel expression. In synaptically coupled myenteric neurons, nicotinic fast excitatory postsynaptic currents are occluded during activation of endogenously co-expressed P2X channels. Our data provide a molecular basis and a synaptic context for cross-inhibition between transmitter-gated channels.