Vagal neurotransmission to the ferret lower oesophageal sphincter: inhibition via GABA_B receptors

Abstract

1 GABA B receptors modulate the function of the lower oesophageal sphincter (LOS) in vivo by inhibiting neurotransmitter release in the vagal pathway controlling LOS relaxation. We aimed to determine whether this e ect was mediated peripherally on vagal motor out¯ow to the ferret LOS in vitro.2 The LOS, with intact vagal innervation, was prepared from adult ferrets and LOS tension measured. Vagal stimulation (0.5 ± 10 Hz, 30 V) evoked a tetrodotoxin-sensitive, frequencydependent relaxation. 3 Both GABA (3610 74 M) and (+)baclofen (2610 74 M) inhibited vagally-stimulated LOS relaxation. The potent GABA B receptor-selective agonist 3-APPA dose-dependently inhibited vagally-stimulated LOS relaxation, with an EC 50 value of 0.7 mM. 4 Decreased responses following vagal stimulation in the presence of (+)baclofen or 3-APPA were reversed with the potent GABA B receptor antagonist CGP 62349. 5 Neither CGP 62349 nor muscimol (GABA A receptor agonist) alone a ected LOS responses following vagal stimulation. 6 Agonists of other G protein-coupled receptors (clonidine (a 2 -adrenoceptor) (5610 76 M), U50488 (k opioid) (10 75 M), neuropeptide Y (10 76 M)) did not a ect vagally-mediated LOS relaxation. 7 The present study supports a discrete presynaptic inhibitory role for GABA B receptors on vagal preganglionic ®bres serving inhibitory motorneurones in the ferret LOS.

Relationship between the mechanism of gastro‐oesophageal reflux and oesophageal acid exposure in patients with reflux disease

“…[20][21][22] Recent interest has focused on c-aminobutric acid type B (GABA B ) receptor agonist baclofen that acts on both central and peripheral [23][24][25] receptors on vagal afferents, which are hypothesized to mediate triggering of TLOSRs. [20][21][22] Recent interest has focused on c-aminobutric acid type B (GABA B ) receptor agonist baclofen that acts on both central and peripheral [23][24][25] receptors on vagal afferents, which are hypothesized to mediate triggering of TLOSRs.…”

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

“…The involvement of GABA B R in the inhibition of transient LES relaxations is attributed to activation of GABA B R present in the dorsal vagal complex (10,11), vagal mechanosensitive afferent neurons (11 -13), and vagal motor neurons innervating LES (14). In ferret LES, baclofen has been shown to reduce vagal output at two peripheral sites, presynapti- Fig.…”

“…Furthermore, the compound has been proposed to be useful as a therapeutic agent for the management of reflux disease (9). The mechanism underlying the effect of GABA B R agonist has been proposed based on functional studies showing that involvement of GABA B R in transient LES relaxations is attributed to the presence of GABA B R in the dorsal vagal complex (10,11), vagal mechanosensitive afferent neurons (11 -13), and vagal motor neurons innervating the LES (14). However, it is not known if GABA B R is present in the LES itself; therefore it remains to be determined whether the GABA B R agonists act at the central nervous system and/or the level of the periphery.…”

NMDA and GABA receptors as potential targets in cough hypersensitivity syndrome

“…Lesogaberan, which is a GABA B agonist that acts only peripherally because it is inactivated centrally by GABA transporters, has been reported to have modest effect on gastrooesophageal reflux disease (GORD) symptoms but did not have the central nervous side-effects associated with baclofen [102], confirming the peripheral action of this new GABA B agonist. Direct inhibitory effects of GABA B receptor agonists on the excitability of vagal afferent nerves in the oesophagus and stomach have been reported [103][104][105]. Interestingly, lesogaberan inhibited inhaled citric acid induced cough in the conscious normal guinea-pig [90], suggesting that this effect may be derived from activation of GABA B receptors perhaps in vagal C-fibres where they have been reported [106,107], and also including effects on vagal afferent nerves in the oesophagus.…”