Role of 5-HT receptors in treatment of overactive bladder.

Normal bladder function requires coordinated detrusor relaxation and urethral sphincter contraction during the filling phase and the reverse during micturition. This is achieved by the integration of excitatory, inhibitory, and sensory nerve activity in control centers in the spinal cord, pons, and forebrain. It is possible that much of bladder pathology is related to disturbances in the vesical ganglia, sensory reflex loops, and central control of micturition. Experimental studies in animals have revealed that spinal reflex circuits involved in voiding function exhibit a dense serotonergic innervation, multiple 5-HT receptors, and sensitivity to 5-HT receptor agonists and antagonists, and 5-HT reuptake inhibitors. Activity in the serotonergic pathway generally enhances urine storage by facilitating the vesical sympathetic reflex pathway and inhibiting the parasympathetic voiding pathway. Thus, 5-HT receptor antagonists and reuptake inhibitors represent important targets for the development of new treatments of detrusor overactivity and urinary incontinence. Among the drugs modulating the bladder function through 5HT receptor, duloxetine, a potent and selective inhibitor of 5-HT and NE reuptake, is presently undergoing clinical trials for stress urinary incontinence after being shown to be effective in animal models of this condition.