Yoshimura Naoki, Bennett Nelson E, Hayashi Yukio, Ogawa Teruyuki, Nishizawa Osamu, Chancellor Michael B, de Groat William C, Seki Satoshi
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
J Neurosci. 2006 Oct 18;26(42):10847-55. doi: 10.1523/JNEUROSCI.3023-06.2006.
Nerve growth factor (NGF) has been proposed as an important mediator inducing bladder overactivity under pathological conditions such as spinal cord injury, bladder outlet obstruction, or cystitis. We therefore examined the effects of chronic NGF treatment on bladder activity and the properties of bladder afferent neurons. In adult female rats, NGF (2.5 microg/microl) was infused continuously into the intrathecal space at the L6-S1 level of spinal cord for 1 or 2 weeks using osmotic pumps (0.5 microl/h). Bladder afferent neurons were labeled with axonal transport of Fast Blue injected into the bladder wall. After intrathecal injection of NGF, cystometrograms under an awake condition showed bladder overactivity revealed by time-dependent reductions in intercontraction intervals and voided volume. ELISA analyses showed significant increases in NGF levels in L6-S1 dorsal root ganglia of NGF-treated rats. In patch-clamp recordings, dissociated bladder afferent neurons exhibiting tetrodotoxin (TTX)-resistant action potentials from NGF-treated animals were larger in diameter and had significantly lower thresholds for spike activation compared with sham rats. In addition, the number of TTX-resistant action potentials during 600 ms depolarizing pulses was significantly increased time dependently after 1 or 2 weeks of NGF application. The density of slowly inactivating A-type K+ currents was decreased by 52% in bladder afferent neurons with TTX-resistant spikes after 2 week NGF treatment. These results indicate that increased NGF levels in bladder afferent pathways and NGF-induced reduction in A-type K+ current density could contribute to the emergence of bladder overactivity as well as somal hypertrophy and hyperexcitability of bladder afferent neurons.
神经生长因子（NGF）被认为是在脊髓损伤、膀胱出口梗阻或膀胱炎等病理状况下诱导膀胱过度活动的重要介质。因此，我们研究了慢性NGF治疗对膀胱活动及膀胱传入神经元特性的影响。在成年雌性大鼠中，使用渗透泵（0.5微升/小时）将NGF（2.5微克/微升）持续注入脊髓L6-S1节段的鞘内空间1或2周。通过向膀胱壁注射Fast Blue进行轴突运输来标记膀胱传入神经元。鞘内注射NGF后，清醒状态下的膀胱压力容积测定显示，随着收缩间期和排尿量的时间依赖性减少，出现了膀胱过度活动。ELISA分析显示，NGF处理大鼠的L6-S1背根神经节中NGF水平显著升高。在膜片钳记录中，与假手术大鼠相比，来自NGF处理动物的表现出对河豚毒素（TTX）耐受动作电位的离体膀胱传入神经元直径更大，动作电位激活阈值显著更低。此外，在应用NGF 1或2周后，600毫秒去极化脉冲期间TTX耐受动作电位的数量随时间显著增加。NGF处理2周后，具有TTX耐受动作电位的膀胱传入神经元中缓慢失活的A型钾电流密度降低了52%。这些结果表明，膀胱传入通路中NGF水平升高以及NGF诱导的A型钾电流密度降低可能导致膀胱过度活动的出现，以及膀胱传入神经元的胞体肥大和兴奋性增高。
