Glycine transporter type 2 (GlyT2) inhibitor ameliorates bladder overactivity and nociceptive behavior in rats.
Glycine transporter type 2 (GlyT2) inhibitor ameliorates bladder overactivity and nociceptive behavior in rats.
复制标题
2 型甘氨酸转运蛋白 (GlyT2) 抑制剂可改善大鼠膀胱过度活动和伤害性行为。
DOI：
10.1016/j.eururo.2012.01.044
复制
发表时间：
2012
期刊：
影响因子：
23.4
通讯作者：
Yoshimura,Naoki
中科院分区：
文献类型：
--
作者：
Yoshikawa,Satoru;Oguchi,Tomohiko;Funahashi,Yasuhito;deGroat,WilliamC;Yoshimura,Naoki
背景：甘氨酸是脊髓中一种主要的抑制性神经递质，其浓度受两种类型的甘氨酸转运蛋白（GlyTs）： GlyT1和GlyT2调节。我们假设GlyTs的抑制可以改善膀胱过度活动和/或下尿路的疼痛感觉。目的：探讨GlyT抑制剂对大鼠膀胱过度活动和疼痛行为的影响。设计、环境和参与者：在尿素麻醉下对环磷酰胺（CYP）治疗的大鼠进行膀胱测量。在有意识大鼠的行为学研究中，通过膀胱内给药树脂干扰素（3μM）诱导伤害反应。选择性GlyT1或GlyT2抑制剂在鞘内施用以评估其效果。测量：测量膀胱测量参数，伤害性行为（舔和冷冻），以及脊髓背侧（L6-S1） GlyTs和甘氨酸受体（GlyR）亚基的信使RNA （mRNA）水平。结果与局限性：在cyp治疗大鼠的膀胱测量过程中，ALX-1393（一种选择性GlyT2抑制剂）引起收缩间期和排尿压力阈值的显著增加，而sarcos（一种GlyT1抑制剂）则没有引起。这些作用被士的宁完全逆转，一种GlyR拮抗剂。ALX-1393也以剂量依赖的方式显著抑制伤害性行为。在假手术大鼠中，GlyT2 mRNA在脊髓背侧的表达水平远高于GlyT1 mRNA（23倍）。在cyp处理的大鼠中，GlyT2和GlyR α1和β亚基的mRNA水平显著降低。结论：这些结果表明，GlyT2在脊髓细胞外甘氨酸的清除中起主要作用，GlyT2抑制可改善cypp诱导的膀胱过度活动和疼痛行为。GlyT2可能成为治疗膀胱过度活动和/或膀胱超敏性疾病（如膀胱疼痛综合征/间质性膀胱炎）的新靶点。
BACKGROUND: Glycine is a major inhibitory neurotransmitter in the spinal cord, the concentration of which is regulated by two types of glycine transporters (GlyTs): GlyT1 and GlyT2. We hypothesized that the inhibition of GlyTs could ameliorate bladder overactivity and/or pain sensation in the lower urinary tract. OBJECTIVE: Investigate the effects of GlyT inhibitors on bladder overactivity and pain behavior in rats. DESIGN, SETTING, AND PARTICIPANTS: Cystometry was performed under urethane anesthesia in cyclophosphamide (CYP)–treated rats. In behavioral studies using conscious rats, nociceptive responses were induced by intravesical administration of resiniferatoxin (3μM). Selective GlyT1 or GlyT2 inhibitors were administered intrathecally to evaluate their effects. MEASUREMENTS: Cystometric parameters, nociceptive behaviors (licking and freezing), and messenger RNA (mRNA) levels of GlyTs and glycine receptor (GlyR) subunits in the dorsal spinal cord (L6–S1) were measured. RESULTS AND LIMITATIONS: During cystometry in CYP-treated rats, significant increases in intercontraction interval and micturition pressure threshold were elicited by ALX-1393, a selective GlyT2 inhibitor, but not by sarcosine, a GlyT1 inhibitor. These effects were completely reversed by strychnine, a GlyR antagonist. ALX-1393 also significantly suppressed nociceptive behaviors in a dose-dependent manner. In sham rats, GlyT2 mRNA was expressed at a much higher level (23-fold) in the dorsal spinal cord than GlyT1 mRNA. In CYP-treated rats, mRNA levels of GlyT2 and the GlyR α1 and β subunits were significantly reduced. CONCLUSIONS: These results indicate that GlyT2 plays a major role in the clearance of extracellular glycine in the spinal cord and that GlyT2 inhibition leads to amelioration of CYP-induced bladder overactivity and pain behavior. GlyT2 may be a novel therapeutic target for the treatment of overactive bladder and/or bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis.