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The Journal of Neuroscience, June 1, 1999, 19(11):4644-4653

Increased Excitability of Afferent Neurons Innervating Rat Urinary Bladder after Chronic Bladder Inflammation

Naoki Yoshimura and William C. de Groat

Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

The properties of bladder afferent neurons in L₆ and S₁ dorsal root ganglia of adult rats were evaluated after chronic bladder inflammation induced by 2 week treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp recordings revealed that most (70%) of the dissociated bladder afferent neurons from control rats were capsaicin sensitive, with high-threshold long-duration action potentials that were not blocked by tetrodotoxin (TTX; 1 µM). These neurons exhibited membrane potential relaxations during voltage responses elicited by depolarizing current pulses and phasic firing during sustained membrane depolarization. After CYP treatment, a similar proportion (71%) of bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes. However, the neurons were significantly larger in size (diameter 29.6 ± 1.0 µm vs 23.6 ± 0.8 µm in controls). TTX-resistant bladder afferent neurons from CYP-treated rats exhibited lower thresholds for spike activation (25.4 ± 0.5 mV) than those from control rats (21.4 ± 0.9 mV) and did not exhibit membrane potential relaxation during depolarization. Seventy percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited tonic firing (average 12.3 ± 1.4 spikes during a 500 msec depolarizing pulse) versus phasic firing (1.2 ± 0.2 spikes) in normal bladder afferent neurons. Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent neurons mimicked the changes in firing properties after CYP treatment. The peak density of an A-type K⁺ current (I_A) during depolarizations to 0 mV in TTX-resistant bladder afferent neurons from CYP-treated rats was significantly smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the inactivation curve of the I_A current was displaced to more hyperpolarized levels by ~15 mV after CYP treatment. These data suggest that chronic inflammation induces somal hypertrophy and increases the excitability of C-fiber bladder afferent neurons by suppressing I_A channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.

Key words: dorsal root ganglion; tetrodotoxin; A-type K⁺ channels; urinary bladder; cyclophosphamide; inflammation; capsaicin

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19114644-10$05.00/0

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