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. 1999 Jun 1;19(11):4644-53.
doi: 10.1523/JNEUROSCI.19-11-04644.1999.

Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation

N Yoshimura  1 , W C de Groat
Affiliations

Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation

N Yoshimura et al. J Neurosci. .

Abstract

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 microM). 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 micrometer vs 23.6 +/- 0.8 micrometer 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 (IA) 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 IA current was displaced to more hyperpolarized levels by approximately 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 IA channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.

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Figures

Fig. 1.
Fig. 1.
Characteristics of action potentials in capsaicin-sensitive bladder afferent neurons with TTX-resistant action potentials from control (A) and CYP-treated cystitis rats (B). The left panelsare voltage responses and action potentials evoked by 30 msec depolarizing current pulses injected through the patch pipette in current-clamp conditions. Asterisks with dashed linesindicate the thresholds for spike activation (−20 mV inA and −29 mV in B). In A, # indicates that the neuron (24 μm in diameter) from the control rat exhibited membrane potential relaxation during depolarizing current injections, which was not detected in the neuron (31 μm in diameter) from the CYP-treated rat (B). The middle panels show the effects of TTX application (1 μm) on action potentials. The right panels show firing patterns during membrane depolarization (500 msec of duration). The current intensity was set to the threshold value for inducing single spikes with 5 msec current pulses as indicated in middle panels. The pulse protocols are shown in theinsets.
Fig. 2.
Fig. 2.
Effects of 4-AP, an IAchannel blocker, on voltage responses, TTX-resistant action potentials, and firing characteristics of a bladder afferent neuron from a control rat. A, Predrug control. B, After 4-AP application (1 mm). The top panels are voltage responses and action potentials evoked by 15 msec depolarizing current pulses injected through the patch pipette in current-clamp conditions. The bottom panels are firing characteristics of action potentials during membrane depolarization (500 msec of duration). Note that action potentials in this neuron were evoked at thresholds (dashed lines) of −20 and −27 mV in the absence and presence of 4-AP, respectively, and that trains of action potentials (i.e., tonic pattern of firing) occurred after 4-AP application (B, bottom tracing), but only a single action potential was evoked before 4-AP application (A, bottom tracing).
Fig. 3.
Fig. 3.
Characteristics of IAcurrent in bladder afferent neurons with TTX-resistant action potentials. Inward currents were suppressed by equimolar substitution of choline for Na+ ions and reduction of Ca2+ ions in the external solution.A–C, One neuron from a control rat.D–F, One neuron from a CYP-treated rat.A and D show superimposed outward K+ currents evoked by voltage steps to 0 mV from holding potentials of −100, −60, and −40 mV in the neurons from control (A) and CYP-treated rats (D). B and E show time dependence of the decay phase of IAcurrents in the neurons from control (B) and CYP-treated rats (E).IA currents were obtained by subtraction of the K+ currents evoked by depolarization to 0 mV from holding potentials of −40 and −120 mV [−120-(−40)]. C and Fshow the effects of 4-AP (2 mm) onIA currents in TTX-resistant bladder afferent neurons from control (C) and CYP-treated rats (F). The IAcurrents were obtained by the subtraction method described above. Two traces are shown in each record: (1) tracing obtained by subtraction of the currents evoked from two holding potentials [−120-(−40)], and (2) tracing obtained by subtraction of total outward K+ currents evoked from −120 mV holding potential before and after 4-AP application (4-AP). Note that the two current traces in each record are similar, indicating that 4-AP suppressesIA currents in both control and CYP-treated rats. The pulse protocols are shown in the insets.
Fig. 4.
Fig. 4.
Steady-state activation and inactivation characteristics of IA current in bladder afferent neurons with TTX-resistant spikes from control and CYP-treated rats. A, Inactivation characteristics ofIA current in control animals (n = 9) (▴) and CYP-treated animals (n = 10) (▵). Relative peak conductance ofIA currents normalized to the maximal conductance of IA currents (G/Gmax) were plotted against membrane potentials. Vh andk were obtained by fitting curves using the modified Boltzmann equation. B, Activation characteristics ofIA current obtained in the neurons from control animals (n = 9) (▪) and CYP-treated animals (n = 10) (■). RelativeIA conductances normalized to the maximalIA conductance (G/Gmax) were plotted against membrane potentials. Note that Vhfor IA inactivation in the neurons from CYP-treated rats (−90.2 mV) was displaced to more hyperpolarized levels than those from control rats (−74.2 mV).
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