Glutamatergic Mechanisms Controlling Lower Urinary Tract Function

Ionotropic glutamatergic antagonists for N-methyl-D-aspartate (NMDA) receptors or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors administered via intravenous, intracerebroventricular, or intrathecal route increases the volume threshold for inducing micturition (V-T), 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 V-T than wild-typemice. The systemic administration of an mGluR5 antagonist markedly increases V-T 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 V-T; and (iii) afferent/ascending pathways from the bladder via mGluR1a and mGluR5 are involved in mechanosensory signal transmission.