5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon

doi:10.1016/0014-2999(96)00297-X

European Journal of Pharmacology

Volume 308, Issue 2, 18 July 1996, Pages 173-180

https://doi.org/10.1016/0014-2999(96)00297-X Get rights and content

Abstract

The pathways and possible transmitters involved in the contractile response to selective 5-HT₃ and 5-HT₄ receptor stimulation in the guinea-pig proximal colon were studied. In the presence of methysergide, 5-HT induced contractions, yielding a biphasic concentration-response curve that was changed into a monophasic curve in the presence of the 5-HT₃ receptor antagonist, granisetron (1 μM) (low-affinity phase blocked), or the 5-HT₄ receptor antagonist, SB 204070 ((1-butyl-4-piperidinyl methyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate) (10 nM) (high-affinity phase blocked) combination of the two antagonists abolished the contraction to 5-HT. The effectiveness and selectivity of both antagonists was confirmed by testing them against contractions in response to the 5-HT₃ receptor-selective agonist, 2-methyl-5-HT, and the 5-HT₄ receptor-selective agonist, 5-methoxytryptamine. Hexamethonium (100 μM) did not affect the 5-HT₃ receptor-mediated contractions, whereas tetrodotoxin (0.3 μM) caused only slight inhibition. Both in the absence and presence of tetrodotoxin, atropine (0.3 μM) inhibited the 5-HT₃ receptor-mediated contractions. Hence, the contractions to 5-HT are partly mediated by 5-HT₃ receptors that are localized on the nerve endings of the motor neurons. Hexamethonium halved the 5-HT₄ receptor-mediated contractions, whereas tetrodotoxin abolished them. The 5-HT₄ receptor-mediated contractions were inhibited by atropine (0.3 μM). Thus, the 5-HT₄ receptors seem to be localized in the soma of the motor neurons; they also occur on interneurons. The remaining contractions induced by 5-HT₃ and 5-HT₄ receptor stimulation in the presence of atropine were almost completely inhibited by the tachykinin NK₁ receptor antagonist, CP 96345 ((2S,3S)-cis-2-(diphenyl methyl)-N-[(2-methoxy phenyl)-methyl]-1-azabicyclo-[2.2.2]-octan-3-amine) (0.1 μM). CP 96345 also abolished or strongly inhibited contractions in response to substance P (10 nM) and to neurokinin A (30 nM), but neither granisetron nor SB 204070 affected them. Hence, stimulation of either 5-HT₃ or 5-HT₄ receptors induced contractions that are partially mediated by acetylcholine, and partially by a tachykinin NK₁ receptor-stimulating neurotransmitter, probably substance P and/or neurokinin A.

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It is possible that at high concentrations fadolmidine provokes α2-adrenergic responses despite the presence of atipamezole. A blockade of the contractile effects by tetrodotoxin indicates a neuronally mediated response by the release of neurotransmitters like acetylcholine and tachykinins, such as substance P (Briejer and Schuurkes, 1996; Ramirez et al., 1994; Yamano and Miyata, 1996). In anaesthetised rats, IV doses of fadolmidine induced an atipamezole and prazosin sensitive increase in MAP followed by reflectory bradycardia mirroring in vitro binding and functional responses of fadolmidine via α2- and α1-adrenergic receptors, respectively.
Fadolmidine is an α₂-adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α₂-adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT₃ receptor prompted functional studies on 5-HT₃. According to the binding affinity data, fadolmidine demonstrated partial agonism on the 5-HT₃ receptor in transfected cells and in guinea pig ileum preparation. However, intravenous (IV) fadolmidine did not produce any 5-HT₃-related hemodynamic effects in anaesthetised rats. In urodynamic studies, intrathecal (IT) fadolmidine interrupted volume-evoked voiding cycles and induced overflow incontinence at high concentrations in anaesthetised rats; however, at the analgesic dose range, the effects were mild. The effects of fadolmidine on kidney function were studied in conscious rats after IV and IT dosing. While IT fadolmidine increased dose-dependent urine output, sodium ion concentration, IV doses increased only sodium ion concentration The effects of IT fadolmidine on heart rate (HR), mean arterial pressure (MAP) and sedation were evaluated in the home cage and in the open field using a telemetry system. In resting conditions, fadolmidine decreased HR dose-dependently and increased initial MAP, whereas in actively moving rats, there were no effects at analgesic doses. The results suggest that at anticipated analgesic clinical doses, IT fadolmidine provides analgesia without significant adverse effects on sedation, MAP or HR and with only modest effects on kidney function and urodynamics.
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On the other hand, intra-raphe injection of SP reduces serotonergic terminal field 5-HT levels. At the GIT level, it has been demonstrated that NK1 receptor desensitization (Ramirez et al., 1994) or antagonism of NK1 receptors (Briejer and Schuurkes, 1996), attenuates the contractile effect of a “selective” 5-HT3 receptor agonist (2-methyl 5-HT) in the presence of atropine in both the guinea pig longitudinal muscle-myenteric plexus preparation and in guinea pig proximal colon. At the level of vagal afferents, it has been demonstrated that prior treatment with a peripherally acting (Sendide) or a CNS-penetrating (CP99,994) NK1 receptor antagonist, reduces the ability of 5-HT or its brain-penetrating analog 2-methyl 5-HT to increase abdominal vagal nerve activity in a vomit-competent species, the ferret (Minami et al., 1998; Minami et al., 2001).
Significant electrophysiological and biochemical findings suggest that receptor cross-talk occurs between serotonergic 5-HT₃- and tachykininergic NK₁-receptors in which co-activation of either receptor by ineffective doses of their corresponding agonists (serotonin (5-HT) or substance P (SP), respectively) potentiates the activity of the other receptor to produce a response. In contrast, selective blockade of any one of these receptors attenuates the increase in abdominal vagal afferent activity caused by either 5-HT or SP. This interaction has important implications in chemotherapy-induced nausea and vomiting (CINV) since 5-HT₃- and NK₁-receptor antagonists are the major classes of antiemetics used in cancer patients receiving chemotherapy. The purpose of this study was to demonstrate whether the discussed interaction produces effects at the behavioral level in a vomit-competent species, the least shrew. Our results demonstrate that pretreatment with either a 5-HT₃ (tropisetron)- or an NK₁ (CP99,994)-receptor specific antagonist, attenuates vomiting caused by a selective agonist (2-methyl 5-HT or GR73632, respectively) of both emetic receptors. In addition, relative to each antagonist alone, their combined doses were 4–20 times more potent against vomiting caused by each emetogen. Moreover, combined sub-maximal doses of the agonists 2-methyl 5-HT and GR73632, produced 8–12 times greater number of vomits relative to each emetogen tested alone. However, due to large variability in vomiting caused by the combination doses, the differences failed to attain significance. The antiemetic dose–response curves of tropisetron against both emetogens were U-shaped probably because larger doses of this antagonist behave as a partial agonist. The data demonstrate that 5-HT₃- and NK₁-receptors cross-talk to produce vomiting, and that synergistic antiemetic effects occur when both corresponding antagonists are concurrently used against emesis caused by each specific emetogen.
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Co-stimulation of 5-HT3 and nACh or 5-HT4 and nACh receptors had a strong excitatory effect on cells, resulting in a significant increase in the amplitude and frequency of firing rate. These findings indicated a possible co-assembly of serotonergic and cholinergic receptors (Legay et al., 1984; Briejer and Schuurkers, 1996; Foxx-Orenstein et al., 1998). Excitation of 5-HT4 receptors only, in conjunction with μACh receptors, was able to initiate long-lasting phasic contractions.
A mathematical model of visceral perception was constructed, comprising primary sensory, motor, intestinofugal and principal neurons, interstitial cells of Cajal and smooth muscle elements that are arranged in a functional circuit through chemical synapses. The mathematical description of constructive elements was based on detailed morphological, anatomical, electrophysiological and neuropharmacological characteristics of cells and chemical processes of electrochemical coupling. Emphasis was given to signal transduction mechanisms that involved multiple neurotransmitters and receptor polymodality. The role of co-transmission by acetylcholine (ACh), serotonin (5-HT), noradrenalin (NA), N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and their corresponding receptors—muscarinic and nicotinic type ACh receptors, β-adrenoceptors, 5-HT_3/4 type serotonergic receptors, NMDA and AMPA receptors in pathogenesis of nociception was studied numerically. Results of computer simulations reproduced patterns of electrical activity of neurons and mechanical responses of the smooth muscle similar to those observed in in vivo and in vitro experiments when ACh, 5-HT, NA, NMDA and AMPA were acting either alone or co-jointly. The results provide neurochemical bases for explanation of pathophysiological mechanisms of visceral nociception, which cannot be elucidated by existing experimental methods. Care should be taken though when extrapolating the numerical results onto the actual system because of limiting assumptions of the model.
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Background. The dopamine D₂ receptor antagonist levosulpiride is a substituted benzamide derivative, whose gastrokinetic properties are exploited clinically for the management of functional dyspepsia. However, for other benzamide derivatives, such as cisapride and mosapride, agonism towards serotonin 5-HT₄ receptors is considered the main mechanism leading to gastrointestinal prokinesia.
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Materials and methods. Circular muscle strips from gastric antrum, and colonic longitudinal muscle strips were used to detect electrically stimulated neurogenic contractions. The effect of levosulpiride was assessed in the absence and presence of GR125487, a selective 5-HT₄ receptor antagonist. Furthermore, potential interaction of levosulpiride with 5-HT₃ receptors and tissue cholinesterases was assessed in unstimulated ileal longitudinal muscle-myenteric plexus preparations.
Results. Antral and colonic strip contractions were cholinergic/tachykinergic in nature. Micromolar concentrations of levosulpiride potentiated submaximal responses, through a mechanism competitively antagonized by GR125487 (pK_B=9.4). In LMMPs, levosulpiride slightly affected contractions caused by the 5-HT₃ receptor agonist 2-methyl-5-HT, and had no effect on contractions to exogenous acetylcholine.
Conclusions. Our results indicate that levosulpiride acts as a moderate agonist at the 5-HT₄ receptor. This property, together with antagonism at D₂ receptors, may contribute to its gastrointestinal prokinetic effect.
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This chapter focuses on gastrointestinal prokinetic agents. Prokinetic agents are promising agents for the treatment of functional bowel disorders. Until now their use was limited because of a poor prokinetic activity and side effects. They are administered to selected patients according to a recognized classification such as ROME II classification for functional dyspepsia and irritable bowel syndrome. For both syndromes, about 30 to 50% of patients may exhibit a motor defect that can be treated by prokinetic agents. The most widely known serotonergic agent used for the treatment of dyspepsia is a mixed 5-HT₃ antagonist and 5-HT4 agonist, cisapride. Both 5-HT₃ and 5-HT₄ receptors are involved in the control of gut motility. They are located on afferent nerves pre- or postsynaptically, enhancing the release of acetylcholine (Ach) and substance P (SP) in response to afferent nerve stimulation. The chapter discusses the treatment of upper gastrointestinal symptoms and the treatment of constipation. It also presents an overview of Cholecystokinin (CCK) antagonists. CCK is a logical target for pharmacotherapy of proximal gastrointestinal tract motility. CCK is released from intestinal cells in response to specific food components including fasty acids and amino acids.
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5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon

Abstract

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Gastroenterology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Gastroenterology

Reg. Pept.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Neuropeptides

Gastroenterology

Reg. Pept.

5-Hydroxytryptamine releases adenosine 5′-triphosphate from nerve varicosities isolated from the myenteric plexus of the guinea-pig ileum

Br. J. Pharmacol.

Pharmacological characterization of 5-hydroxytryptamine receptor types in the guinea-pig proximal colon

J. Gastroint. Motil.

Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum

Evidence for two distinct release mechanisms

Naunyn-Schmied. Arch. Pharmacol.

The pharmacological characterization of 5-HT3 receptors in three isolated preparations derived from guinea-pig tissues

Br. J. Pharmacol.

5-HT₃ and 5-HT₄ receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon

The pharmacological characterization of 5-HT₃ receptors in three isolated preparations derived from guinea-pig tissues