Involvement of metabotropic glutamate 5 receptor in visceral pain.
Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague-Dawley rats were subjected to repeated, isobaric CRD (12 x 80 mmHg, for 30s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1-10 micromol/kg, i.v.) and MTEP (1-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52+/-8% (p<0.01) and 25+/-11% (p<0.05), respectively, without affecting colonic compliance. MPEP (10 micromol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33+/-9% (p<0.01) and 35+/-8% (p<0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0-5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55-78% by 10 microM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10 microM MTEP (p<0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.
Lindström
Erik
E
AstraZeneca R&D, Mölndal, Sweden Nerve Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, University of Adelaide, Australia Discipline of Medicine, School of Molecular and Biomedical Sciences, University of Adelaide, Australia Discipline of Physiology, School of Molecular and Biomedical Sciences, University of Adelaide, Australia.
Brusberg
Mikael
M
Hughes
Patrick A
PA
Martin
Christopher M
CM
Brierley
Stuart M
SM
Phillis
Benjamin D
BD
Martinsson
Rakel
R
Abrahamsson
Christina
C
Larsson
Håkan
H
Martinez
Vicente
V
Blackshaw
Ashley L
AL
D000818:Animals; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D003106:Colon / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D041981:Gastrointestinal Tract / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D010528:Peristalsis / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013153:Splanchnic Nerves / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017833:Visceral Afferents / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate