Targeting serotonin and norepinephrine receptors in stress urinary incontinence.
Stress urinary incontinence (SUI) in women is prevalent, and there are no globally developed or widely approved drugs for the disease. One strategy for improving urinary continence is to augment the function of the urethral rhabdosphincter through neuropharmacology. The present review describes the innervation of the urethra, and the role of the central nervous system in controlling nerve activity. Targeting serotonin and norepinephrine (or noradrenaline) receptors in Onuf's nucleus is shown to augment the function of the urethral rhabdosphincter by increasing pudendal nerve efferent activity. It is proposed that the ability of serotonin and norepinephrine to enhance the effects of glutamate (the primary excitatory neurotransmitter for pudendal sphincter motor neurons) while having no direct effects of their own, allow facilitation of rhabdosphincter activity during urine storage while allowing complete relaxation during micturition. Duloxetine, a potent and balanced dual serotonin (5-HT)-norepinephrine reuptake inhibitor (SNRI), potentiates these physiological effects of endogenous serotonin and norepinephrine (by inhibiting the reuptake of these neurotransmitters in the pre-synaptic element) and thereby enhances the central nervous system's natural continence control mechanisms.
Laboratory of Neurourology, Duke University, Chief Scientific Officer, Dynogen Pharmaceuticals, Inc, Durham, NC, USA. kthor@dynogenpharma.com
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D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000344:Afferent Pathways / Q000187:drug effects; D005260:Female; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism* / Q000502:physiology; D011941:Receptors, Adrenergic / Q000187:drug effects* / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014521:Urethra / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D014550:Urinary Incontinence, Stress / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects / Q000502:physiology
D018759:Adrenergic Uptake Inhibitors; D009638:Norepinephrine; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors