Roles of Glycinergic and Gamma‐aminobutyric‐ergic Mechanisms in the Micturition Reflex in Rats

Abstract

The micturition reflex is one of the autonomic reflexes mediated by the spinobulbospinal reflex pathway that passes through the pontine micturition center. In the central nervous system, glutamate is a major excitatory amino acid, while glycine and gamma-aminobutyric acid (GABA) are major inhibitory neurotransmitters and act to inhibit the micturition reflex at supraspinal and/or spinal sites. Glycine and GABA have additive or synergistic inhibitory effects on bladder activity. Hypofunction of glycinergic/GABAergic mechanisms in the lumbosacral spinal cord induces voiding dysfunctions, such as detrusor overactivity (DO) or detrusor-sphincter dyssynergia (DSD) after spinal cord injury (SCI) or bladder outlet obstruction in rats. Intrathecal, intravenous, or dietary glycine inhibits both bladder and urethral activity in normal and spinal cord injury (SCI) rats. Therefore, glycine might be a useful agent for the treatment of DO. Intrathecal muscimol and baclofen (GABA(A) and GABA(B) agonists, respectively) also inhibit non-voiding bladder contractions by suppressing C-fiber bladder afferents in SCI rats. They also improve DSD by suppressing Onuf's nucleus and C-fiber bladder afferents. Baclofen is approved for the treatment of DO in SCI patients, but this agent has not been widely used because the therapeutic window of the drug is modest and the dose is limited by side-effects. Glutamic acid decraboxylase (GAD), the GABA synthesis enzyme, gene delivery by using non-replicating herpes simplex virus (HSV) vectors inhibits DO by suppressing C-fiber bladder afferents without affecting voiding contraction in SCI rats. Therefore, GAD gene therapy can restore urine storage function without affecting voiding function; it would be more beneficial than drug therapy for the treatment of urinary problems in SCI patients.