A novel role for the metabotropic glutamate receptor-7: modulation of faecal water content and colonic electrolyte transport in the mouse.
OBJECTIVE
Increasing evidence implicates metabotropic glutamate receptor mGlu(7) in the pathophysiology of stress-related disorders such as depression and anxiety. Mood disorders are frequently associated with gastrointestinal (GI) dysfunction; however, the role of mGlu(7) receptors outside the CNS is unknown. This present study investigated the expression and possible functional role of mGlu(7) receptors in the mouse colon.


METHODS
Expression of mGlu(7) receptor mRNA and protein was studied in mouse colon by in situ hybridization and Western blotting. Effects of the selective mGlu(7) receptor agonist AMN082 on defecation and faecal parameters were studied in an isolation-induced stress model. AMN082 effects on ion transport and neuronal intracellular signalling were examined via Ussing chambers and calcium imaging.


RESULTS
mGlu(7) receptor mRNA and protein were highly expressed in colon mucosa. Stress-induced faecal output was unaffected by AMN082, although faecal water content was increased. In mucosa/submucosa preparations, 100 nM and 1 microM AMN082 increased bethanechol-induced changes in short-circuit current in the Ussing chamber. This was sensitive to tetrodotoxin. Also, 100 nM AMN082 significantly increased calcium signalling in a subset of submucosal neurons.


CONCLUSIONS
Activating mGlu(7) receptors increased colonic secretory function in vivo and ex vivo. In a group of submucosal neurons, AMN082 strongly induced calcium signalling and the presence of submucosal nerves was required for the AMN082-dependent increase in secretion. These data suggest that targeting mGlu(7) receptors may be useful in the treatment of central components of stress disorders and also stress-associated GI dysfunction such as diarrhoea or constipation.
Julio-Pieper
M
M
Alimentary Pharmabiotic Centre, University College Cork, Ireland.
Hyland
N P
NP
Bravo
J A
JA
Dinan
T G
TG
Cryan
J F
JF
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects; D003106:Colon / Q000378:metabolism*; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004573:Electrolytes / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000503:physiopathology*
D001559:Benzhydryl Compounds; D004573:Electrolytes; D018690:Excitatory Amino Acid Agonists; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7