The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception

Abstract

In micturition control, the roles of ionotropic glutamate (iGlu) receptors NMDA and AMPA are well established, whereas little is known about the function of metabotropic glutamate (mGlu) receptors. Since antagonists for mGlu5 receptors are efficacious in animal models of inflammatory and neuropathic pain, we examined whether mGlu5 receptors play a role in the voiding reflex and bladder nociception and, if so, via centrally or peripherally localized receptors. The mGlu5 receptor antagonist MPEP dose-dependently increased the micturition threshold (MT) volume in the volume-induced micturition reflex (VIMR) model in anesthetized rats. Following doses of 5.2, 15.5 and 51.7 μmol/kg of MPEP (intraduodenal), the MT was increased by 24.7 ± 5.0%, 97.2 ± 12.5% ( P < 0.01) and 128.0 ± 28.3% ( P < 0.01) from the baseline, respectively ( n = 4–5; compared with 0.8 ± 9.1% in the vehicle group). Infusing MPEP (0.3, 1 mM) directly into the bladder also raised MT. However, the efficacious plasma concentrations of MPEP following intravesical dosing were similar to that after intraduodenal dosing (EC 50 of 0.11 and 0.27 μM, respectively, P > 0.05). MPEP also dose-dependently attenuated the visceromotor responses (VMR, total number of abdominal EMG spikes during phasic bladder distension) in anesthetized rats. The VMR was decreased to 1332.4 ± 353.9 from control of 2886.5 ± 692.2 spikes/distension ( n = 6, P < 0.01) following MPEP (10 μmol/kg, iv). Utilizing the isolated mouse bladder/pelvic nerve preparation, we found that neither MPEP (up to 3 μM) nor MTEP (up to 10 μM) affected afferent discharge in response to bladder distension ( n = 4–6). In contrast, MPEP attenuated the responses of the mesenteric nerves to distension of the mouse jejunum in vitro. These data suggest that mGlu5 receptors play facilitatory roles in the processing of afferent input from the urinary bladder, and that central rather than peripheral mGlu5 receptors appear to be responsible.