Thor Karl B
Dynogen Pharmaceuticals, Inc., Durham, North Carolina 27709, USA.
Urology. 2003 Oct;62(4 Suppl 1):3-9. doi: 10.1016/s0090-4295(03)00754-4.
Stress urinary incontinence (SUI), the most common form of incontinence, continues to be a largely underdiagnosed problem that imposes large financial and quality-of-life burdens on many women but has few treatment options. Ongoing animal and early human studies have shown that monoamine neurotransmitters play key roles in controlling urethral storage and micturition reflexes. Motor neurons found in the Onuf nucleus of the sacral spinal cord control urethral function, and have several unique properties that distinguish them from other motor neurons. First, the neurons are uniformly smaller than other surrounding motor neurons and have bundled dendrites, allowing strong synchronous activation or inhibition. Second, the neurons demonstrate unique neurochemical profiles. Unlike neurons in surrounding areas, the motor neurons of the Onuf nucleus have dense populations of noradrenergic and serotonergic terminals. Animal studies have shown that alpha1-adrenoceptors and serotonin (5-hydroxytryptamine [5-HT]) receptors in the Onuf nucleus facilitate sphincter contraction. Agonists that stimulate these receptors facilitate the guarding or incontinence reflex, whereas antagonists that block the receptors inhibit this reflex. Therefore, boosting the effects of 5-HT and norepinephrine (NE) to enhance sphincter activity could be clinically promising for improving the symptoms of SUI. Importantly, the activity of the sphincter neurons can be increased pharmacologically during urine storage without interfering with bladder-sphincter synergy. Administering the 5-HT/NE uptake inhibitor duloxetine facilitates sphincter contraction during bladder filling but not during bladder contraction in micturition. This unique effect of duloxetine may be maintained by the selective neuromodulatory effects of 5-HT and NE on activation of sphincter motor neurons by the neurotransmitter glutamate. Prolonging the effect of naturally released NE and 5-HT with duloxetine could augment the body's normal processes for controlling urine storage and micturition. Early trials have demonstrated that duloxetine significantly reduces incontinence episodes and is well tolerated in the clinical setting.
压力性尿失禁（SUI）是最常见的尿失禁形式，仍然是一个在很大程度上未被充分诊断的问题，给许多女性带来了巨大的经济负担和生活质量负担，但治疗选择却很少。正在进行的动物研究和早期人体研究表明，单胺类神经递质在控制尿道储尿和排尿反射中起关键作用。在骶髓Onuf核中发现的运动神经元控制尿道功能，并且具有一些使其与其他运动神经元区分开来的独特特性。首先，这些神经元比周围的其他运动神经元普遍更小，并且具有成束的树突，从而能够实现强烈的同步激活或抑制。其次，这些神经元表现出独特的神经化学特征。与周围区域的神经元不同，Onuf核的运动神经元有密集的去甲肾上腺素能和5-羟色胺能（5-HT）终末。动物研究表明，Onuf核中的α1-肾上腺素能受体和5-羟色胺（5-羟色胺[5-HT]）受体促进括约肌收缩。刺激这些受体的激动剂促进自主控制或失禁反射，而阻断这些受体的拮抗剂则抑制该反射。因此，增强5-羟色胺和去甲肾上腺素（NE）的作用以增强括约肌活动在临床上可能有望改善SUI的症状。重要的是，在尿液储存期间，可以通过药理学方法增加括约肌神经元的活性，而不会干扰膀胱-括约肌协同作用。给予5-羟色胺/NE摄取抑制剂度洛西汀可促进膀胱充盈期间的括约肌收缩，但在排尿时膀胱收缩期间则不然。度洛西汀的这种独特作用可能通过5-羟色胺和NE对神经递质谷氨酸激活括约肌运动神经元的选择性神经调节作用来维持。用度洛西汀延长天然释放的NE和5-羟色胺的作用可能会增强身体控制尿液储存和排尿的正常过程。早期试验表明，度洛西汀可显著减少失禁发作次数，并且在临床环境中耐受性良好。
