Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Abstract

1 The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. 2 In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 ± 4.00 mmol kg 71 , i.v.) and the selective CB 1 -receptor agonist HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg 71 h 71 ) and 2-deoxy-D-glucose (1.25 mmol kg 71 , i.v.). By contrast, neither WIN 55,212-2 (1 ± 4 mmol kg 71 , i.v.) nor HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.) did modify histamine-induced acid secretion (20 mmol kg 71 h 71 ). The selective CB 2 -receptor agonist JWH-015 (3 ± 10 mmol kg 71 , i.v.) was ine ective. 3 The gastric antisecretory e ects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB 1 -receptor antagonist SR141716A (0.65 mmol kg 71 , i.v.) and una ected by the selective CB 2 -receptor antagonist SR144528 (0.65 ± 2 mmol kg 71 , i.v.). 4 Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg 71 , i.v., followed by continuous infusion of 10 mg kg 71 h 71 ) signi®cantly reduced, but not abolished, the maximal inhibitory e ect of HU-210 (0.3 mmol kg 71 , i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg 71 , i.v.) did not modify the antisecretory e ect of HU-210. 5 Immunoreactivity to the CB 1 receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB 2 receptor-like immunoreactivity was not observed. 6 These results indicate that gastric antisecretory e ects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB 1 receptors, located on pre-and postganglionic cholinergic pathways. However, the ine ectiveness of atropine in reducing the e ect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB 1 receptors.

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…For example they inhibit GI transit and motility in rats (Landi et al, 2002), decrease the intragastric pressure and the pyloric contractility by activating CB 1 receptors (Krowicki et al, 1999), tonically inhibit colonic propulsion (Pinto et al, 2002) and decrease GI transit in mice (Izzo et al, 2000). CB 1 receptor agonists decreased the gastric acid secretion induced by pentagastrin given intravenously (Adami et al, 2002), but i.c.v. injection of the synthetic non-selective agonist WIN 55,212-2 was ineffective in preventing the pentagastrin stimulated gastric acid secretion (Adami et al, 2004).…”

“…Cannabinoids were shown to inhibit gastrointestinal motility (Izzo et al, 1999;Krowicki et al, 1999), gastric acid secretion (Adami et al, 2002) and development of gastric mucosal lesions both in acid-dependent (Germano et al, 2001;Rutkowska and Fereniec-Goltbiewska, 2006) and acid-independent ulcer models (Shujaa et al, 2009). Accordingly, CB 1 receptors were identified in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons, moreover, CB 1 receptors are also identified in the dorsal vagal complex: in the nucleus of the solitary tract (NTS) (Partosoedarso et al, 2003), in the dorsal motor nucleus of vagus (DMNV) (Mackie, 2005) and prominently, in the area postrema (Mackie, 2005).…”

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

“…Similarly, CB 1 -receptor activation by the potent agonist HU-210 reduced neurogenic ion transport elicited by the proinflammatory peptide kallidin (15). Gastric secretion evoked by pentagastrin and 2-deoxy-D-glucose was also inhibited by CB 1 receptor agonists, and the receptor was identified on myenteric cholinergic neurons and/or vagal pathways in the myenteric plexus (1). These studies have recently been extended to show that endogenous cannabinoids play a role in the regulation of fluid secretion.…”

“…However, recent reports (1,15,40) suggest that cannabinoid (CB) receptors of the CB 1 subtype may also suppress neurally evoked secretion. Tyler et al (40) showed that CB 1 receptors could reduce secretion evoked by electrical field stimulation (EFS) but not that evoked by acetylcholine in the rat ileum.…”

Sistema cannabinoide y regulación de la conducta alimentaria

“…La distribución de los receptores CB1 similar a la de la grelina o al péptido similar al glucagon (GLP1, glucagon like peptide 1) y en estructuras neurales modulando transmisión colinérgica y no colinérgica (Adami, Frati, Bertini, Kulkarni-Narla, Brown, de Caro et al 2002;Storr, Gaffal, Saur, Schusdziarra y Allescher, 2002), sugieren que forman parte de las conexiones entre tubo digestivo y cerebro regulando la conducta alimentaria.…”