Involvement of metabotropic glutamate 5 receptor in visceral pain

Abstract 

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 (12×80 mmHg, for 30s with 5min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1–10μmol/kg, i.v.) and MTEP (1–3μmol/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 (10μmol/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 (0–5g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55–78% by 10μM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10μM 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.

Keywords: Colorectal distension, Visceral pain, Visceromotor response, Colonic afferents, mGluR5, Glutamate