Glutamatergic Mechanisms Controlling Lower Urinary Tract Function

Abstract

Ionotropic glutamatergic antagonists for N‐methyl‐d‐aspartate (NMDA) receptors or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors administered via intravenous, intracerebroventricular, or intrathecal route increases the volume threshold for inducing micturition (VT), decreases bladder contraction pressure, suppresses external urethral sphincter (EUS) electromyogram (EMG) activity concomitant with bladder contractions, and decreases voiding efficiency. The intrathecal injection of a metabotropic glutamate receptor (mGluR) antagonist for group I/II (mGluR1, mGluR5/mGluR2, mGluR3) facilitates EUS EMG activity without affecting bladder contractions. Mice lacking mGluR1a exhibit facilitated EUS EMG activity, which presents a prominent tonic component superimposed on bursting activity during voiding, and have larger VT than wild‐type mice. The systemic administration of an mGluR5 antagonist markedly increases VT without altering voiding pressure. These results suggest that: (i) NMDA and AMPA glutamatergic mechanisms in the central nervous system play essential roles in controlling lower urinary tract functions; (ii) the spinal mGluR1a mechanism has an inhibitory input to sphincter motor nuclei to suppress tonic EUS activity during VT; and (iii) afferent/ascending pathways from the bladder via mGluR1a and mGluR5 are involved in mechanosensory signal transmission.