Submitted on August 1, 2006
Accepted on October 11, 2006
Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5
Richard L Young1*, Amanda Page2, Tracey A O'Donnell3, Nicole J Cooper3, and L Ashley Blackshaw2
1 Department of Gastroenterology, Hepatology & General Medicine, Royal Adelaide Hospital, Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
2 Department of Gastroenterology, Hepatology & General Medicine, Royal Adelaide Hospital, Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia; Discipline of Physiology, University of Adelaide, Adelaide, South Australia, Australia
3 Department of Gastroenterology, Hepatology & General Medicine, Royal Adelaide Hospital, Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia
* To whom correspondence should be addressed. E-mail: richard.young{at}adelaide.edu.au.
Metabotropic glutamate receptors (mGluR) are classified into Group I, II and III mGluR. Group I (mGluR1, mGluR5) are excitatory whilst Group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations (TLESR) and gastroesophageal reflux. TLESR are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist MPEP. mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension mucosal (TM) receptors. MPEP (1-10 µM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmole, icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 were abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
