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The Journal of Neuroscience, October 18, 2006, 26(42):10847-10855; doi:10.1523/JNEUROSCI.3023-06.2006

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Behavioral/Systems/Cognitive
Bladder Overactivity and Hyperexcitability of Bladder Afferent Neurons after Intrathecal Delivery of Nerve Growth Factor in Rats

Naoki Yoshimura,^1,2 Nelson E. Bennett,¹ Yukio Hayashi,¹ Teruyuki Ogawa,^1,3 Osamu Nishizawa,³ Michael B. Chancellor,¹ William C. de Groat,² and Satoshi Seki^1,2,3

Departments of ¹Urology and ²Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and ³Department of Urology, Shinshu University, Matsumoto 390-0802, Japan

Correspondence should be addressed to Dr. Naoki Yoshimura, Department of Urology, University of Pittsburgh School of Medicine, Suite 700, Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213. Email: nyos{at}pitt.edu

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 µg/µl) 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 µl/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.

Key words: nerve growth factor; rat; dorsal root ganglion; urinary bladder; Na⁺ current; K⁺ current

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Received July 17, 2006; revised Sept. 1, 2006; accepted Sept. 1, 2006.

Correspondence should be addressed to Dr. Naoki Yoshimura, Department of Urology, University of Pittsburgh School of Medicine, Suite 700, Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213. Email: nyos{at}pitt.edu

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