Site of action of GABA(B) receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats.
OBJECTIVE
Stimulation of gamma-aminobutyric acid B metabotropic receptors (GBRs) by baclofen reduces the incidence of transient lower esophageal sphincter (LES) relaxations. The GBR effect may be a result of a central site of action in the dorsal vagal complex, where upper gastrointestinal vagal reflexes are integrated. Therefore, we first localized GBR immunostaining in the dorsal vagal complex. Next, we tested the hypothesis that baclofen modulates LES motor tone via GBR expressed by vagal efferent neurons.


METHODS
An antibody against the human GBR1b isoform was characterized and used for immunocytochemistry in rats and ferrets. Functional studies involved microinjection of L-glutamate into the caudal dorsal motor nucleus of the vagus to evoke an LES relaxation in decerebrate unanesthetized ferrets.


RESULTS
In both species, GBR1b was expressed in preganglionic motor neurons and, in ferrets, the receptor was highly expressed in identified LES-projecting preganglionic neurons. GBR1b immunostaining was also pronounced in the subnucleus centralis of the nucleus tractus solitarius. This distribution implicates GBR in control of the esophageal phase of swallowing at the level of the central program generator. In functional studies, centrally evoked LES relaxation (-73% +/- 8% mm Hg) was significantly attenuated after 7 micromol/kg intravenous baclofen (-37% +/- 10%; N = 5).


CONCLUSIONS
These data all suggest that GBR agonists inhibit LES relaxation via a site of action associated with vagal motor outflow to the LES.
McDermott
C M
CM
Department of Pharmacology and Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.
Abrahams
T P
TP
Partosoedarso
E
E
Hyland
N
N
Ekstrand
J
J
Monroe
M
M
Hornby
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001418:Baclofen / Q000494:pharmacology; D015153:Blotting, Western; D004943:Esophagogastric Junction / Q000737:chemistry / Q000294:innervation / Q000502:physiology*; D005289:Ferrets; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000032:analysis / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology*
D018080:Receptors, GABA-B; D001418:Baclofen