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. 1999 Jun 1;517(Pt 2):599–605. doi: 10.1111/j.1469-7793.1999.0599t.x

Prolonged enhancement of the micturition reflex in the cat by repetitive stimulation of bladder afferents

Chong-He Jiang 1, Sivert Lindström 1
PMCID: PMC2269345  PMID: 10332105

Abstract

  1. Prolonged modulation of the parasympathetic micturition reflex was studied in cats anaesthetized by α-chloralose. Reflex discharges were recorded from a thin pelvic nerve filament to the bladder and evoked by stimulation of the remaining ipsilateral bladder pelvic nerves or urethral branches of the pudendal nerve.

  2. Stimulation of bladder or urethral afferents at Aδ intensity evoked micturition reflexes with a latency of 90-120 ms. Such reflexes were much enhanced following repetitive conditioning stimulation of the same afferents at 20 Hz for 5 min.

  3. The reflex enhancement lasted more than 1 h after the conditioning stimulation. The effect was not prevented by a preceding complete transection of the sympathetic supply to the bladder. A prolonged suppression of the reflex was obtained after conditioning stimulation of afferents in the dorsal clitoris nerves.

  4. It is proposed that the prolonged modulations of the micturition reflex represent physiological adaptive processes, which preserve a flawless function of the bladder during life. The observations provide a theoretical explanation for the beneficial effect of electric nerve stimulation in patients with voiding disorders.

Activity-dependent modulation of synaptic transmission has been studied extensively in several mammalian neuronal systems, notably in the hippocampus, neocortex, cerebellum, spinal cord and autonomic ganglia (Teyler & DiScenna, 1987; Bennett, 1994; Linden, 1994; Wang et al. 1997). Recently, we have observed prolonged modulations of the parasympathetic micturition reflex in rats. The effects were demonstrated as changes in the cystometric micturition threshold volume. The threshold decreased significantly after a period of field stimulation of bladder mechanoreceptor afferents, the same afferents that drive the normal micturition reflex (Jiang & Lindström, 1996). The opposite effect, a prolonged increase in threshold volume, was seen after stimulation of afferents with known inhibitory effects on the micturition reflex (Jiang & Lindström, 1998).

These modulations seem to involve the central transmission of the micturition reflex (Jiang, 1998). The physiological sensitivity of the stimulated afferents was unaffected and so was the effectiveness of the peripheral motor part of the reflex. Furthermore, the threshold decrease could be prevented by prior injection of an NMDA antagonist. These studies were initiated to provide a theoretical rationale for the use of neuromodulatory techniques as treatment for voiding disorders in man (Kaplan & Richards, 1986; Fall & Lindström, 1991; Katona, 1992; Madersbacher & Ebner, 1992; Primus et al. 1996).

In the present study we have extended the analysis by recording the micturition reflex response directly from bladder efferents in the cat. The reflex was evoked by selective stimulation of bladder and urethral afferents. In this way, the specificity of the effect could be examined and the assumption of a central site of modulation verified. Furthermore, it was found that not only the threshold but also the reflex amplitude was modified by the conditioning stimulation.

METHODS

Seven adult female cats, 3-4 kg, were used. They were initially anaesthetized with ketamine (Ketalar, Parke-Davis AS; 15 mg kg−1i.m.) and xylazine (Rompun vet., Bayer AG; 1 mg kg−1i.m.) followed by α-chloralose (55 mg kg−1i.v.) at the end of the surgery. To maintain a stable level of anaesthesia for the entire experiment, two animals received a continuous i.v. infusion of α-chloralose (2 mg kg−1 h−1), the others small intermittent doses (2-5 mg kg−1) as required. With both procedures, an adequate depth of anaesthesia was ascertained by the lack of blood pressure and heart rate changes to strong paw pinches. The femoral artery and vein were cannulated to allow blood pressure recordings and fluid injections, and a tracheotomy was performed to ensure safe respiration. Mean arterial blood pressure was kept above 120 mmHg by a slow i.v. infusion of a bicarbonate-buffered Ringer-glucose solution. Heart rate was monitored by ECG. Temperature was maintained at 38°C by a feedback-controlled heating lamp. Individual experiments lasted for 12-27 h. The animals were killed at the end of the experiment by an overdose of the anaesthetics followed by severance of the heart. The experiments were approved by the Animal Research Ethical Committee of Linköping in agreement with Swedish law.

The bladder neck and proximal urethra were exposed extraperitoneally by a low mid-line incision. A thin catheter was inserted into the bladder through a slit in the proximal urethra and used to adjust bladder volume and to monitor bladder pressure (Fig. 1). Once catheterized, the bladder was allowed to drain through the open catheter to avoid unintentional bladder contractions. It remained empty with unloaded afferents for at least 5 h before the start of stimulation. On the right side, a small bladder pelvic nerve branch was transected close to the bladder wall. The central end was mounted on a pair of electrodes for multi-unit recordings of bladder efferent activity. The remaining ipsilateral pelvic nerve branches to the bladder were freed from connective tissue and mounted on a pair of stimulation electrodes while left in continuity with both the bladder and the spinal cord. Branches directed towards the urethra (or other visceral organs) were excluded. In two of seven cats, the urethral branches of the right pudendal nerve branch were dissected and mounted for afferent stimulation. In three other experiments the dorsal clitoris nerves on both sides were exposed for stimulation. The remaining two cats had the sympathetic chains and hypogastric nerves transected bilaterally in order to exclude sympathetic contributions to the studied reflex effects (Mazières et al. 1998). The exposed nerves were isolated from the surrounding tissue by a thin plastic sheath and by body-warm paraffin oil in a pool formed by sewn-up skin flaps.

Figure 1. Schematic diagram of experimental arrangements.

Figure 1

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Reflex discharges were recorded in a transected thin bladder branch of the right pelvic nerve following electrical stimulation of Aδ afferents in the remaining ipsilateral pelvic nerve fibres to the bladder. In two animals, similar reflexes were evoked by stimulation of urethral branches of the pudendal nerve. Inhibitory effects were induced in three experiments by stimulation of the dorsal clitoris nerves. Two animals had their hypogastric nerves and sympathetic chains transected bilaterally. Further details are given in the text.

Test reflex discharges were evoked by stimulation of the appropriate nerves by an isolated constant current stimulator, using a train of three stimuli at 10 ms intervals and a stimulus repetition rate of 1 Hz. In most trials the stimulation intensity was adjusted to give a maximal Aδ reflex response (< 300 μA with 0.2 ms pulses). In three cats, small test responses could be evoked while the bladder was empty and open; in the other experiments it was necessary to provide some background facilitation of the reflex from ongoing activity in bladder mechanoreceptor afferents. Such activity was obtained by filling the bladder with saline from a reservoir, which was elevated to give an isotonic bladder pressure just below threshold for spontaneous bladder contractions (< 1 kPa). Evoked test reflexes were pre-amplified (× 1000) with a custom-made differential amplifier (cut-off frequency, 5 kHz) and displayed on a digital chart recorder (Hioki 8830). The signal was also full-wave rectified, digitized (AT-MIO-16F-5, National Instruments) at a sampling rate of 0.5 or 0.7 kHz, averaged (20 or 32 responses) and stored on a PC (LabVIEW 3.0 software). Averaged reflexes were quantified off-line by determining the area under the curve by summing digitized values for a time period of 100 ms from reflex onset (after subtraction of baseline).

Once stable reflex discharges had been recorded for 10-20 min an attempt was made to modulate the test reflex by tetanic conditioning stimulation. To that end the same afferents were stimulated repetitively for 5 min, using single stimuli at 20 Hz. In the standard procedure, the stimulation intensity was the same as that evoking a maximal Aδ test response. The sampling of test reflexes was then resumed and continued for at least 1 h or until a new trial with conditioning stimulation. Several trials of conditioning stimulation were performed in each experiment at different stimulation intensities and intervals (from 20 min to 8 h). In three experiments, conditioning stimulation of afferents in the dorsal clitoris nerve (10 Hz, 5 min) was tried in an attempt to induce a prolonged depression of the test reflex.

The effect of the conditioning stimulation was evaluated by comparing the mean size of six consecutive averaged reflexes, obtained during a 15 min control period prior to the conditioning, with the same number of consecutive reflexes sampled during a similar period at the peak effect. Student's paired t test was used for statistical analysis of stimulation outcome in individual experiments. To allow comparison between experiments, the values were normalized and expressed as a percentage of the control using the Wilcoxon signed rank test for group comparison.

RESULTS

Reflex discharges with a latency of 90-120 ms were evoked in bladder motor fibres by stimulation of ipsilateral bladder pelvic afferents at Aδ intensity (Fig. 2A). Such reflex responses are the electrophysiological equivalents of the normal micturition reflex (De Groat, 1975). The long latency of the response is due to a polysynaptic spinobulbar-spinal reflex pathway (Barrington, 1921). In two experiments, similar bladder reflex responses were evoked by stimulation of urethral afferents in the pudendal nerve (Mazières et al. 1997).

Figure 2. Effect of conditioning stimulation on the micturition reflex.

Figure 2

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A, upper trace shows a test response evoked by a train of three constant current stimuli (0.2 ms, 10 ms apart) applied to the ipsilateral bladder pelvic nerves. The stimulus repetition rate was 1 Hz and the intensity 30 μA, maximal for the Aδ reflex response. The middle trace is the same response full-wave rectified. The lower trace is an average of 20 consecutive rectified test reflex responses. B, similar responses as in A but evoked 20 min after a period of conditioning stimulation of the same bladder pelvic nerves. The conditioning consisted of 5 min of continuous repetitive stimulation at 20 Hz (single stimuli) at the same intensity as for the test response. The bladder was filled with 8 ml of saline. Time calibration in B refers to all traces.

The test Aδ reflexes were greatly enhanced following repetitive conditioning stimulation of the activating afferents (20 Hz for 5 min; Fig. 2B). Since individual reflex responses varied considerably in amplitude, the effect was quantified by averaging a number of consecutive rectified responses (Fig. 2, bottom traces). The size of the reflex was then determined by integrating the area under the curve of the averaged response. Using this procedure, the conditioned reflex response in Fig. 2B was almost 3 times as large as the control reflex (280%). There was a similar highly significant increase in the reflex response in each individual animal (P < 0.001, paired t test). Based on trials with optimal conditioning parameters, the reflexes increased to a mean of 310% (range, 170-460%) for the seven experiments (P < 0.05 for group effect, Wilcoxon signed rank test). The enhancement was about the same (270%) in the two animals with bilateral transection of the sympathetic supply to the bladder (Methods) as in those with an intact sympathetic system (330%). Thus, the sympathetic system was not critical for the reflex modulation.

The conditioning stimulation itself evoked vigorous discharges in the bladder efferents. No reflex enhancement was obtained when the stimulation intensity or the excitability of the micturition reflex was below threshold for such activity. The optimal enhancement seemed to occur with conditioning stimuli of the same intensity as that giving a maximal test reflex. There was no obvious change in the reflex threshold following the conditioning stimulation. Thus, the reflex enhancement was not due to a decrease in electrical threshold of the afferents at the site of stimulation.

In most trials, the reflex enhancement developed rather gradually (Fig. 3). Although some facilitation was evident immediately after the conditioning stimulation, the maximal effect typically occurred 10-20 min later. In all experiments, the enhancement lasted for more than 1 h, the longest interval systematically explored. Repeated trials with conditioning stimulation within this time period were ineffective, unless the first conditioning stimulation was delivered at sub-optimal intensity. Thus, conditioning stimulation at maximal intensity for 5 min seemed to saturate the enhancement process. After long resting periods (4 and 8 h), a second conditioning stimulation again induced a significant reflex enhancement (two experiments). This observation suggests that there was a partial recovery from the original enhancement at these long intervals. In both cases, however, the recording filament had to be remounted between the two stimulation sessions so this interpretation is only tentative.

Figure 3. Time course and selectivity of micturition reflex enhancement.

Figure 3

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Records in A show test reflexes evoked before (upper pair of traces) and 20 min after a period of conditioning stimulation of the bladder pelvic nerves (BPN) as in Fig. 2 (lower pair of traces). Each trace is the average of 32 consecutive test reflexes. The upper response in each pair was evoked by stimulation of bladder Aδ afferents (3 × 200 μA), the lower response by stimulation of urethral afferents (3 × 500 μA). The stimulation intensity was in both cases adjusted to give a maximal reflex discharge. The time calibration is for all records. B shows the time course of reflex enhancement after the same conditioning stimulation. The reflex size was determined from the area under the averaged response curve and normalized with respect to the mean prestimulus size. Reflexes evoked by bladder afferent stimulation are indicated by •, those from urethral afferents by ○. The bladder was empty and open throughout.

In the experiment illustrated in Fig. 3, a small test reflex was also evoked by stimulation of urethral afferents. This reflex response was not facilitated by conditioning stimulation of bladder pelvic afferents (Fig. 3B, ○). The opposite result was obtained in a trial with the reversed procedure applying the conditioning stimulation to urethral afferents. In this case, the reflex from urethral afferents was enhanced to 150% while the reflex from bladder afferents was unchanged (100%). Urethral afferent stimulation induced reflex enhancement in two more trials in another experiment (330%). These results indicate that reflex modulation could be elicited by urethral afferents, possibly with some degree of pathway specificity. At the least, the enhancement was not due to a general increase in central excitability.

The latter concern was motivated by the fact that the micturition reflex is very anaesthesia sensitive, although less so for α-chloralose (Rudy et al. 1991). Its long duration of action is another advantage with this anaesthetic. In the cat, a single dose would typically give a lasting anaesthesia for 8-10 h. This slow metabolism of α-chloralose makes it highly unlikely that the reflex enhancement could be due to changes in the depth of anaesthesia. In agreement with this, there was no difference in effect whether the anaesthetic was given intermittently or continuously (Methods). Extra doses of α-chloralose (2.5-10 mg kg−1i.v.) on top of those required for a stable anaesthesia did not abolish the prolonged reflex enhancement (3 experiments). Furthermore, there was no indication of unspecific changes in arousal following the conditioning stimulation i.e. changes in blood pressure, heart rate, breathing or other motor responses. Thus, the observed reflex enhancement could not be accounted for by unspecific changes in the state of the animal.

As a further test of specificity, conditioning stimulation was applied to afferents in the dorsal clitoris branch of the pudendal nerve. Such afferents are known to have an inhibitory effect on the micturition reflex (Fall & Lindström, 1991) and to give a prolonged increase in the micturition reflex threshold (Jiang & Lindström, 1999). As shown in Fig. 4, an enhanced reflex response could effectively be suppressed by conditioning stimulation of these afferents (10 Hz, 5 min). After 25 min, a reflex response was restored by the infusion of 10 ml saline into the bladder, thereby increasing the background facilitation of the micturition reflex (Methods). In this situation, a second period of bladder pelvic nerve stimulation restored the reflex response to the level before the inhibition. A similar effect of dorsal clitoris nerve stimulation with complete long lasting abolition of the reflex response was obtained in another conditioning session in the same experiment. In two other animals, the dorsal clitoris stimulation produced only partial suppression of the micturition reflex to a mean of 30% (three trials) for the first averaged reflex immediately after the conditioning stimulation. In these cases, the reflex suppression was only temporary and the response returned to the control level within 5-9 min. Presumably, the inhibition was too weak to induce a lasting reflex suppression.

Figure 4. Depression of enhanced micturition reflex by stimulation of afferents in the dorsal clitoris nerve.

Figure 4

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The bladder Aδ reflex was enhanced by conditioning stimulation of the same bladder afferents (BPN, first column), as in Fig. 2 (same experiment). About 60 min later, a second period of conditioning stimulation of afferents in the dorsal clitoris nerve (DC, second bar; 10 Hz, 500 μA, 5 min) completely suppressed the reflex response. The reflex response was partially restored when the bladder, after about 20 min, was filled with an additional 10 ml of saline to the original 8 ml. A third period of conditioning stimulation of bladder afferents completely restored the reflex size to the same level as before the depression. •, normalized reflex response from averages of 20 individual reflexes.

DISCUSSION

A prolonged enhancement of the Aδ micturition reflex was observed in all experiments following a short period of repetitive stimulation of bladder mechanoreceptor Aδ afferents. The opposite effect, a prolonged depression of the micturition reflex, occurred after a corresponding stimulation of inhibitory afferents in the dorsal clitoris branch of the pudendal nerve. These opposing effects on the micturition reflex are, to our knowledge, the first direct electrophysiological demonstration of dynamic long-term modulation of a central parasympathetic reflex. The findings confirm and extend our previous observations of prolonged changes in the micturition threshold in rats following intravesical or intravaginal electric stimulation (Jiang & Lindström, 1996, 1998). Intravesical electric stimulation is a simple procedure for field stimulation of bladder afferents (Ebner et al. 1992). It consistently produced a prolonged decrease in the micturition threshold - a change considered to be indicative of an increased excitability in the central micturition reflex pathway (Jiang, 1998).

The main advantage with the present procedure, compared with that of intravesical stimulation, is that bladder afferents could be activated selectively in a controlled manner. Thereby, unintentional co-activation of other visceral or somatic afferents (or bladder C afferents) could be avoided. Co-activation of unrelated afferents occurred to some extent in all experiments with intravesical stimulation. Although various control experiments indicated that bladder afferents were crucial for the induced modulation of the micturition reflex (Jiang & Lindström, 1996), a specific role of these afferents could only be verified by their selective stimulation. An involvement of the sympathetic system (afferents or efferents) in the modulation was ruled out by the lack of effect of a total bilateral sympathectomy.

In the cat, the micturition reflex is driven exclusively by myelinated bladder afferents (Yoshimura & De Groat, 1997), while in the rat, mechanosensitive C afferents may contribute to the response (Morrison, 1997). In previous rat experiments with intravesical stimulation (Jiang & Lindström, 1996; Jiang, 1998) we tried to avoid co-activation of bladder C afferents by keeping the stimulation intensity below threshold for direct activation of postganglionic (unmyelinated) efferents to the bladder. Even so, it might be difficult to exclude some contribution of C afferents to the modulatory effect. With direct pelvic nerve stimulation, the threshold intensity for a bladder C afferent is more than 10 times higher than that of a maximal Aδ response (Mazières et al. 1998). Thus, the present reflex enhancement clearly occurred without the involvement of C afferents. It may be clinically important that only Aδ afferents were required for the modulatory effect, since it implies that patients may be treated adequately by intravesical electric stimulation without induction of pain. Visceral nociceptors from the pelvic region are associated with C afferents (Cervero, 1994) and cutaneous nociceptors of the Aδ type can be avoided by the use of a large indifferent electrode (anode) on the skin (G. Gladh & S. Lindström, unpublished observations).

The normal micturition reflex is organized as a positive feedback system in which an ongoing bladder contraction is reinforced by contraction-induced activation of bladder mechanoreceptors (Lindström et al. 1984). With such a system, a decrease in the micturition threshold could be caused by a change in gating of the reflex rather than by a change in excitability (gain) of the central reflex pathway. The latter effect would not be revealed by cystometry since the positive feedback system would saturate the micturition response already in the control situation. With direct nerve stimulation, the detrusor-mechanoreceptor link of the positive feedback is bypassed, at least when the bladder is empty and open. Thus, the present increase in the maximal reflex response clearly demonstrates an enhanced excitability in the central micturition reflex pathway.

With fluid in the bladder the situation is potentially more complicated since a reflex enhancement could induce rhythmic ongoing detrusor contractions (Lindström et al. 1984). Such effects were observed in some experiments after repeated conditioning trials (not presented). In these cases the reflex response was reinforced by peripheral feedback excitation during the contractions and suppressed by central inhibition during the intervals between contractions, giving inconsistent variable reflex responses. Since there was no detrusor activity prior to the conditioning stimulation it seems likely that a stimulation-induced central excitability increase was involved in the change in bladder behaviour.

The long duration of the reflex modulation suggests that the change results from a long-term potentiation (LTP)-like increase in the synaptic transmission of the micturition reflex pathway. Support for this assumption comes from the finding that the modulation induced by intravesical stimulation was prevented by prior administration of the specific NMDA antagonist D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (CPPene; Jiang, 1998). Where in the pathway this potentiation takes place remains to be determined. It is quite possible that the observed enhancement represents the cumulative effect of small modulatory changes at several synaptic sites. The micturition reflex is mediated by a polysynaptic spinobulbo-spinal pathway and both the ascending and descending limbs are known to involve glutaminergic excitatory synapses with postsynaptic receptors of both NMDA and non-NMDA type (Matsumoto et al. 1995; Kakizaki et al. 1998). The reflex suppression following stimulation of afferents in the dorsal clitoris nerve may be due either to upgrading of an inhibitory system affecting the micturition reflex or to inhibition-induced long-term depression (LTD) of its excitatory synapses. Both types of mechanism have been observed in other synaptic systems (Yang et al. 1994; Komatsu, 1996).

The present modulation of the micturition reflex may be a reflection of a physiological adaptive process that serves to regulate both the threshold volume and gain of the reflex during normal growth. In man, the micturition threshold volume (functional bladder capacity) increases from about 20 ml at birth to 200-400 ml in the adult, i.e. 10-20 times. On top of this there are large individual variations (by at least a factor of five) depending on differences in night-time diuresis (Mattsson & Lindström, 1995). Changes in urethral resistance will also affect the functional demand on the bladder. Clearly, some dynamic adaptive process would be required to ensure a flawless function of the bladder throughout life. Incomplete bladder emptying increases the risk of urinary tract infections with secondary kidney destruction. So from an evolutionary perspective, a good bladder function would be critical for reproduction and survival of the individual.

It seems likely that the adaptive signals are derived from the activity of bladder mechanoreceptors during normal voidings. After all, stimulation of these afferents produced the observed reflex enhancement. To be effective the duration of the adaptive process should be consistent with the normal voiding behaviour. The rat, for instance, voids 20-30 times a day, i.e. with intervals of about 1 h or less. The finding that the modulation of their micturition threshold lasts for about 1 h fits with this pattern. The cat and man void less frequently, about 5-6 times per day, which means that they would require a more prolonged modulatory effect. In this perspective, it was probably critical for the present findings that the bladders were left empty and resting for at least 5 h before the first conditioning stimulation. The lack of additional reflex enhancement with subsequent conditioning stimulation within an hour agrees with this idea.

In the discussed scenario, the clinical application of intravesical electric stimulation capitalizes on a normal physiological adaptive process. If so, it is easy to understand why the treatment may give a lasting improvement of bladder function. The micturition reflex will initially be upgraded by artificial stimulation of the bladder afferents. Once the patients can void normally, an adequate function will be maintained by daily ‘training sessions’ - the normal voidings - just as in healthy individuals.

Acknowledgments

This study was supported by the County of Östergötland (project no. 94/173) and by the Swedish Medical Research Council (project no. 4767).

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