Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats
Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats
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DOI：
10.1523/jneurosci.3023-06.2006
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发表时间：
2006-10-18
影响因子：
5.3
通讯作者：
Seki, Satoshi
中科院分区：
文献类型：
--
作者：
Yoshimura, Naoki;Bennett, Nelson E.;Seki, Satoshi
神经生长因子（NGF）已被提出作为一个重要的介质诱导膀胱过度活动的病理条件下，如脊髓损伤，膀胱出口梗阻，或膀胱炎。因此，我们研究了慢性神经生长因子治疗对膀胱活动和膀胱传入神经元的特性的影响。在成年雌性大鼠中，使用渗透泵（0.5 μ l/h）将NGF（2.5 μ g/μ l）连续输注到脊髓L 6-S1水平的鞘内空间中1或2周。膀胱传入神经元用注射到膀胱壁中的Fast Blue的轴突运输标记。鞘内注射神经生长因子后，清醒状态下的膀胱测压显示膀胱过度活动，表现为收缩间期和排尿量的时间依赖性减少。ELISA分析表明，在L 6-S1背根神经节的神经生长因子治疗大鼠的神经生长因子水平显着增加。在膜片钳记录，解离膀胱传入神经元表现出河豚毒素（TTX）的抗神经生长因子治疗的动物的动作电位直径较大，并有显着较低的阈值与假手术大鼠相比，尖峰激活。此外，在600 ms去极化脉冲期间的TTX抗性动作电位的数量在NGF应用1或2周后显著增加。NGF处理2周后，具有TTX抗性棘波的膀胱传入神经元的缓慢失活A型K+电流密度降低了52%。这些结果表明，膀胱传入通路中NGF水平的增加和NGF诱导的A型K+电流密度的降低可能导致膀胱过度活动以及膀胱传入神经元的体细胞肥大和过度兴奋。
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 mu g/mu l) 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 mu l/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.