Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs

doi:10.1053/gast.2002.36025

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 1129-1134

https://doi.org/10.1053/gast.2002.36025 Get rights and content

Abstract

Background & Aims: 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 μmol/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.

GASTROENTEROLOGY 2002;123:1129-1134

Section snippets

Transient LES relaxations in dogs

All studies were performed with the approval and within the guidelines of the Animal Ethics Committees of the Göteborg region. Eleven adult male and female Labrador retrievers were recruited to the study. They were retained with the inclusion criterion that the average number of TLESRs should not be less than 4 every 45 minutes during stimulation using parameters detailed later. Cervical esophagostomies were made and after a recovery period, the dogs were used in different drug-screening

Effects of CBR ligands on TLESRs and related parameters

The average number of TLESRs, reflux episodes and other motility parameters for all the control experiments with intravenous (IV) administration are noted in Table 1 (11 dogs, n = 66).

. Control parameters

TLESRs/45 min	Latency to first TLESR (min)	Swallows/45 min	Reflux episodes/45 min
5.7 ± 0.1	4.1 ± 0.3	13.5 ± 1.0	3.7 ± 0.2

The results are based on all IV control experiments in 11 dogs (n = 66) used in the present study.

WIN 55,212-2 (5.7–57 nmol/kg) potently and dose-dependently inhibited TLESRs

Discussion

The present study shows for the first time that CBRs inhibit TLESR and gastroesophageal reflux. The potency of the CBR agonist WIN 55,212-2 we observed was high in comparison with previously reported effects on emesis. For instance, the antiemetic ED₅₀ of WIN 55,212-2 is approximately 1 mg/kg.12, 13 However, WIN 55,212-2 blocked opioid-induced emesis in ferrets with an ED₅₀ of 0.03 mg/kg.¹¹

The agonist reduced the rate of TLESRs without altering their shape (duration, simultaneous esophageal

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^☆: Address requests for reprints to: Anders Lehmann, Ph.D., Gastrointestinal Biology, Integrative Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. e-mail [email protected]; fax: (46) 31 776 3747.

^☆☆: Supported by AstraZeneca R&D Mölndal.

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Basic–Alimentary TractCannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs☆,☆☆

Abstract

Section snippets

Transient LES relaxations in dogs

Effects of CBR ligands on TLESRs and related parameters

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Pharmacol Ther

Gastroenterology

Eur J Pharmacol

Eur J Pharmacol

Life Sci

Gastroenterology

Gastroenterology

Gastroenterology

Eur J Pharmacol

Mol Cell Neurosci

Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects

J Clin Invest

Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists

Am J Physiol

Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-oesophageal reflux disease

Gut

Basic–Alimentary Tract
Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs☆,☆☆

Control of transient lower oesophageal sphincter relaxations and reflux by the GABA_B agonist baclofen in patients with gastro-oesophageal reflux disease