Gastric vasodilatation in the rat by cannabinoid (CB) receptor activation: Involvement of sensory neurons and nitric oxide (NO) (original) (raw)
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Δ9-Tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors
European Journal of Pharmacology, 1999
We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to D 9 -tetrahydrocanna-Ž 9 . 9 binol D -THC in anesthetized rats. Intravenously administered D -THC evoked long-lasting decreases in intragastric pressure and pyloric contractility, bradycardia, and hypotension. The changes in gastric motor function and bradycardia were abolished by vagotomy and ganglionic blockade, whereas spinal cord transection prevented the hypotensive response. Administered intravenously alone, Ž . Ž . Ž . N-piperidin-1-yl -5-4-chlorophenyl -1-2,4-dichlorophenyl -4-methyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB receptor 1 antagonist, evoked transient decrease in intragastric pressure, and hypertension that was associated with bradycardia. However, this agent completely blocked the gastric motor and cardiovascular responses to intravenous D 9 -THC. Application of D 9 -THC to the dorsal surface of the medulla resulted in small and short-lasting decreases in gastric motor and cardiovascular function. We conclude that the decrease in gastric motor function and bradycardia are partially due to an action of D 9 -THC in the dorsal medulla and that intact vagal nerves are required. The hypotension was mediated through sympathetic pathways. Both gastric motor and cardiovascular effects of peripherally administered D 9 -THC seem to be mediated through cannabinoid CB receptors. q 1999 Elsevier Science B.V. All rights reserved. 1 9 Ž
British Journal of Pharmacology, 1998
1. The eect of cannabinoid drugs has been investigated on cholinergic and non-adrenergic noncholinergic (NANC) contractile responses to the circular smooth muscle of guinea-pig ileum elicited by electrical ®eld stimulation (EFS). 2 The cannabinoid receptor agonist WIN 55,212-2 (1 ± 1000 nM) and the putative endogenous ligand anandamide (0.1 ± 100 mM) both produced a concentration-dependent inhibition of the cholinergic (9 ± 57% and 1 ± 51% inhibition) and NANC (9 ± 55% and 2 ± 57% inhibition) contractile responses. WIN 55,212-2 and anandamide did not modify the contractions produced by exogenous acetylcholine or substance P. 3 Apamin (30 nM), a blocker of Ca 2+ -activated K + channels, reduced the inhibitory eect of WIN 55,212-2 on cholinergic, but not NANC, contractile response. N G -nitro-L-arginine methyl ester (100 mM), an inhibitor of nitric oxide synthase, or naloxone (1 mM), an opioid receptors antagonist, did not modify the inhibitory eect of WIN 55,212-2 on both cholinergic and NANC contractions. 4 The inhibitory eects of WIN 55,212-2 and anandamide on both cholinergic and NANC contractile response was competitively antagonized by the cannabinoid CB 1 receptor antagonist SR 141716A (10 ± 1000 nM). 5 In absence of other drugs, SR 141716A (1 ± 1000 nM) enhanced cholinergic (1 ± 45% increase) and NANC (2 ± 38% increase) contractile responses elicited by electrical stimulation, but did not modify the contractions produced by acetylcholine or substance P. 6 It is concluded that activation of prejunctional cannabinoid CB 1 receptors produces inhibition of cholinergic and NANC excitatory responses in the guinea-pig circular muscle. The inhibition of cholinergic (but not NANC) transmission involves activation of apamin-sensitive K + channels. In addition, an endogenous cannabinoid ligand could inhibit cholinergic and NANC transmission in the guinea-pig ileal circular muscle.
Cannabinoid 1 receptors modulate intestinal sensory and motor function in rat
Neurogastroenterology & Motility, 2010
Cannabinoid receptors are involved in visceral pain perception and control of intestinal motility in vivo. The underlying mechanisms are not well characterized. We aimed to determine whether the cannabinoid-1 (CB(1)) receptor modulates intestinal afferent nerve discharge and the peristaltic reflex. Rats were anesthetized and intestinal segments were removed. Afferent nerve discharge from a mesenteric nerve was investigated in vitro in the presence of the CB(1) antagonist SR 141716A or the CB(1) agonist WIN 55212-2. The myenteric peristaltic reflex was induced by electrical field stimulation and influence of SR 141716A or WIN 55212-2 was recorded. Afferent nerve discharge to the algesic mediator bradykinin was reduced to 11 +/- 5.1 imp s(-1) following pretreatment with SR 141716A and unchanged after WIN 55212-2 compared to 63 +/- 15.4 imp s(-1) in controls. At maximum distension pressure (80 cmH(2)O) during ramp distension, 92 +/- 12.4 imp s(-1) were reached following SR 141716A compared to 260 +/- 13.2 in vehicle controls and 227 +/- 15.4 in WIN 55212-2 pretreated animals. In contrast, afferent discharge to 5-HT (500 micromol L(-1)) was increased to 75 +/- 24.6 imp s(-1) following WIN 55212-2 compared to 18 +/- 5.9 imp s(-1) in controls, whereas SR 141716A had no effect. Ascending neuronal contractions were dose-dependently attenuated in the presence of SR 141716A and latency of these contractions was reduced. WIN 55212-2 had opposite effects that were abolished by SR 141716A. Activation of the CB(1) receptor differentially alters afferent intestinal nerve sensitivity to bradykinin, 5-HT, and noxious mechanical distension, while it strengthens ascending neuronal contractions. Further studies are needed to determine the physiological relevance of these observations.
Modulation of gastric acid secretion by cannabinoids in rats
Journal of Biochemical and Molecular Toxicology, 2018
The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2-deoxy-D-glucose (D-G) (200 mg/kg, intravenous) or-carbachol (4 μg/kg, SC) in the 4-hour pylorus-ligated rats. The CB1R agonist (N-arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON-1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D-G and reduced MDA and NO contents with an increase in GSH and PON-1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.
British Journal of Pharmacology, 2009
Background and purpose: Although it is well accepted that cannabinoids modulate intestinal motility by reducing cholinergic neurotransmission mediated by CB1 receptors, it is not known whether the endocannabinoids are involved in more complex circuits and if they interact with other systems. The aim of the present study was to examine possible interactions between cannabinoid CB1 receptors and purines in the control of spontaneous contractility of longitudinal muscle in mouse ileum.Experimental approach: The mechanical activity of longitudinally oriented ileal segments from mice was recorded as isometric contractions.Key results: The selective CB1 receptor agonist, N-(2-chloroethyl)5,8,11,14-eicosaetraenamide (ACEA) reduced, concentration dependently, spontaneous contractions in mouse ileum. This effect was almost abolished by tetrodotoxin (TTX) or atropine. Inhibition by ACEA was not affected by theophylline (P1 receptor antagonist) or by P2Y receptor desensitization with adenosine 5′[β-thio]diphosphate trilithium salt, but was significantly reversed by pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) (P2 receptor antagonist), by P2X receptor desensitization with α,β-methyleneadenosine 5′-triphosphate lithium salt (α,β-MeATP) or by 8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino) bis(1,3,5-naphthalenetrisulphonic acid)] (P2X receptor antagonist). Contractile responses to α,β-MeATP (P2X receptor agonist) were virtually abolished by TTX or atropine, suggesting that they were mediated by acetylcholine released from neurones, and significantly reduced by ACEA.Conclusion and implications: In mouse ileum, activation of CB1 receptors, apart from reducing acetylcholine release from cholinergic nerves, was able to modulate negatively, endogenous purinergic effects, mediated by P2X receptors, on cholinergic neurons. Our study provides evidence for a role of cannabinoids in the modulation of interneuronal purinergic transmission.
2012
El dolor neuropatic es causat per una lesio o malaltia del sistema nervios somatosensiorial, i es caracteritza per la presencia d'alodinia e hiperalgesia. Actualment el seu tractament es basa en la terapia amb opioids, pero son necessaries altes dosis per alleujar el simptomes, les quals van acompanyades de nombrosos efectes secundaris. Aleshores es necessari investigar noves dianes aixi com nous mecanismes per tal de millorar els tractaments amb opioids a fi d’evitar l’administracio de dosis altes i els efectes no desitjats. En aquest estudi hem investigat el paper que juguen dos dels principals neurotransmissors gasosos, l'oxid nitric (NO) i el monoxid de carboni (CO) en el desenvolupament del dolor neuropatic, aixi com dels seus efectes en les terapies mediades per receptors opioids mu (MOR) i delta (DOR), i cannabinoids tipus 2 (CB2). D'aquesta manera, utilitzant la constriccio cronica del nervi ciatic com a model de dolor neuropatic hem demostrat que: I) la via de s...
Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine
British Journal of Pharmacology, 1996
A9-tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.46, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [3H]-CP 55,940 from cannabinoid binding sites. 2 Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50= 1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens. 3 SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 giM) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine. 4 Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2. 5 Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 LM SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940. 6 These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine. 7 THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor. 8 At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.
In-vivo Modulation of Gastrointestinal Motility by Cannabinoid Drugs
Pharmacy and Pharmacology Communications, 2000
Cannabinoid CB 1 receptors have been detected in several peripheral neurons, including those of the myenteric plexus. Activation of myenteric (prejunctional located) cannabinoid CB 1 receptors decreased intestinal motility induced by electrical stimulation in the isolated guinea-pig and human ileum. In-vivo studies have shown that cannabinoid receptor agonists decreased gastrointestinal motility through activation of cannabinoid CB 1 receptors, while SR141716A, a cannabinoid CB 1-receptor antagonist, increased intestinal motility. Both central and peripheral cannabinoid CB 1 receptors could modulate upper gastrointestinal, but the effect of systemic (intraperitoneally injected) cannabinoid drugs was mediated by peripheral receptors. In addition, the potency of cannabinoid receptor agonists was increased during in¯ammatory diarrhoea.