Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons.
OBJECTIVE
Inhibitory G-protein-coupled receptors have demonstrated potential in treatment of gastroesophageal reflux disease (GERD) through actions on vagal afferent signaling. Metabotropic glutamate receptors (mGluR) belong to this receptor family and have great pharmacologic and molecular diversity, with 8 subtypes. We investigated mGluR in the vagal system of humans and other species.


METHODS
Expression of mGluR1-8 in human, dog, ferret, and rodent nodose ganglia was investigated by reverse-transcription polymerase chain reaction. mGluR1-8 immunohistochemistry was performed in combination with retrograde tracing of vagal afferents from ferret proximal stomach to nodose ganglia. Transport of mGluR peripherally was investigated by vagal ligation, followed by immunohistochemistry. Glutamate receptor pharmacology of ferret and rodent gastroesophageal vagal afferents was investigated by testing single fiber responses to graded mechanical stimuli during drug application to their peripheral endings.


RESULTS
Messenger RNA for several mGluR was detected in the nodose ganglia of all species. Retrograde tracing indicated that ferret gastric vagal afferents express mGluR protein. Accumulation of immunoreactivity proximal to a ligature showed that mGluR were transported peripherally in the vagus nerves. Glutamate (1-30 mumol/L with kynurenate 0.1 mmol/L) concentration dependently inhibited vagal afferent mechanosensitivity. This was mimicked by selective group II and III mGluR agonists but not by a group I agonist. Conversely, a group III mGluR antagonist increased mechanosensitivity to intense stimuli.


CONCLUSIONS
Both exogenous and endogenous glutamate inhibits mechanosensitivity of vagal afferents. Group II (mGluR2 and 3) and group III mGluR (mGluR4, 6, 7, 8) are novel targets for inhibition of vagal signaling with therapeutic potential in, for example, GERD.
Page
Amanda J
AJ
Nerve-Gut Research Laboratory, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Young
Richard L
RL
Martin
Chris M
CM
Umaerus
Mia
M
O'Donnell
Tracey A
TA
Cooper
Nicole J
NJ
Coldwell
Jonathan R
JR
Hulander
Malin
M
Mattsson
Jan P
JP
Lehmann
Anders
A
Blackshaw
L Ashley
LA
D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004285:Dogs; D006801:Humans; D008465:Mechanoreceptors / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D009620:Nodose Ganglion / Q000502:physiology; D016133:Polymerase Chain Reaction; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology*
D017931:DNA Primers; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1