α2‐Adrenoceptor as a New Target for Stress Urinary Incontinence

There are few drugs to enhance the urinary continence function under stress conditions such as sneezing, coughing or lifting heavy objects because pharmacological targets for improving urethral closure mechanisms under stress conditions are not fully elucidated. Imipramine and duloxetine have been used clinically to treat stress urinary incontinence (SUI). The mechanisms of these drugs are thought to stimulate serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) receptors by inhibiting reuptake of 5-HT and NE in the Onuf’s nucleus, thereby increasing external urethral sphincter (EUS) activity.1–4 We have recently reported using rats that 5-HT and NE pathways are important to maintain sneeze-induced urethral continence reflexes and that duloxetine-induced enhancement of the reflexes is predominantly mediated by α1-ARs in the spinal cord.5 Previous studies that examined the pelvic-to-pudendal spinal reflex during urine storage 6, 7 have demonstrated that pelvic nerve electrical stimulation or bladder distension induced by saline infusion can induce an increase in EUS activity, which is attenuated by intrathecal or intravenous (i.v.) administration of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. Glutamate is well known as an excitatory neurotransmitter in the central nervous system (CNS), and its release at nerve terminals is regulated by presynaptic α2-ARs in the dorsal horn 8, 9 or sympathetic preganglionic neurons.10 However, the involvement of glutamate and α2-AR systems in the control of urethral closure reflexes induced in stress conditions remains to be explored. Therefore, this review summarizes the results of our recent studies that examined the control of EUS responses in stress conditions by glutamate and/or α2-AR mechanisms.