Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs.
OBJECTIVE
Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal acid reflux, and are triggered by postprandial gastric distention. Stimulation of GABA(B) receptors potently inhibits triggering of TLESR by gastric loads. The functional similarity between GABA(B) and cannabinoid receptors (CBRs) prompted us to study the role of CBRs on mechanisms of gastric distention-induced TLESRs.


METHODS
Gastric nutrient infusion and air insufflation was performed during gastroesophageal manometry in conscious dogs. The effects of the CBR agonist WIN 55,212-2 were assessed alone and in combination with the CBR1 antagonist SR141716A or the CBR2 antagonist SR144528. The effects of WIN 55,212-2 were also studied on firing of gastric vagal mechanosensitive afferents in an isolated preparation of ferret stomach.


RESULTS
WIN 55,212-2 (57 nmol/kg) inhibited the occurrence of TLESR after gastric loads by 80% (P < 0.01). The latency to the first TLESR after the load was prolonged (P < 0.001), and the occurrence of swallowing was reduced (P < 0.05). The CBR1 antagonist SR141716A reversed the effects of WIN 55,212-2, whereas the CBR2 antagonist SR144528 did not. The CBR1 antagonist alone increased occurrence of TLESR (P < 0.05). The responses of gastric vagal mechanoreceptors to distention were unaffected by WIN 55,212-2 at a concentration of 3 micromol/L.


CONCLUSIONS
Exogenous and endogenous activation of the CBR1 receptor inhibits TLESRs. The effects of CBR1 are not mediated peripherally on gastric vagal afferents, and therefore are most likely in the brain stem.
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D004285:Dogs; D004943:Esophagogastric Junction / Q000294:innervation / Q000502:physiology*; D005260:Female; D005289:Ferrets; D058786:GABA-B Receptor Agonists; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000503:physiopathology*; D008024:Ligands; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology
D000700:Analgesics; D048588:Benzoxazines; D058786:GABA-B Receptor Agonists; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant