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【摘要】 Reflex plasticity between pelvic afferent and pudendal efferent nerve fibers was examined in anesthetized rats. Brief high-frequency electric stimulation (300 pulses at 100 Hz) of the pelvic nerve afferent fiber produced a long-lasting potentiation of the pelvic-to-pudendal reflex (PPR). This tetanization-induced potentiation was abolished by a selective N -methyl- D -aspartate (NMDA) receptor antagonist and attenuated by a non-NMDA excitatory amino acid receptor antagonist. However, the GABA A -receptor antagonist had no effect on this potentiation. Both intrathecal glutamate (0.1 mM, 2-5 µl it) and NMDA (0.1 mM, 2-5 µl it) induced a potentiation of PPR similar to that of tetanization. Agonist-induced potentiation was shorter than tetanization-induced potentiation. The duration of the contraction wave of intraurethral pressure, elicited by PPR, was elongated by tetanization-induced potentiation, whereas the peak pressure was not affected. All these results demonstrate that brief high-frequency stimulation of the pelvic nerve afferent fiber can induce a distinct and long-lasting modulation in PPR activity and this change may be involved in nociceptive C afferent-induced obstructive urinary dysfunctions.
【关键词】 pelvic nerve pudendal nerve N methyl D aspartate DL aminohydroxymethylisoxazolepropionic acid
THE EFFICIENCY OF TRANSMISSION at a synapse is not constant, but it can vary depending on both the neuronal circuitry within the nervous system as well as the patterns of ongoing activity ( 29 ). Long-term potentiation (LTP), which is found in a variety of brain structures, characterizes a sustained increase in the efficiency of synaptic transmission in response to a brief period of tetanic activation. LTP in the hippocampus is of interest because of its presumed relationship to memory formation. At the most thoroughly investigated site of LTP expression, the Schaffer collateral synapse in the CA1 region of the hippocampus, the induction of LTP is dependent on the activity of glutamatergic N -methyl- D -aspartate (NMDA)/inophore complex ( 5, 16, 19, 26, 35 ). However, several DL - -amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) receptors (mediated forms of LTP) have been recognized in the neocortex ( 21 ) and within the hippocampus itself ( 5, 19, 26, 32, 35 ).
Another possible related phenomenon, termed "windup," is a progressive increase in the number of action potentials elicited per stimulus that occurs in dorsal horn neurons of the spinal cord under low-frequency repetitive stimulation. Investigations on this phenomenon using spinal slices suggested windup, at least in part, is responsible for the hyperalgesia and allodynia following prolonged noxious stimulation (6, 25, 32, 40-42. However, the limitation of the transverse slice technique, which retained only 3-6 mm of attached dorsal roots, did not permit reliable analysis of afferent fibers responsible for this phenomenon in each case. Furthermore, the destination and physiological relevance of impulses resulting from the potentiated response remain unclear.
Urine storage is one of the important functions of the urinary bladder. During the storage phase of micturition cycles, action potentials induced by bladder distension transmit centripetally onto dorsal horn neurons through pelvic afferent nerve fibers. After integration within the spinal cord, these impulses cause external-urethral sphincter (EUS) contraction via the pudendal efferent nerve (PEN) fiber. This pelvic-to-pudendal reflex (PPR) is essential for urine continence ( 10 ). A recent study on the windup phenomenon, using an intact spinal cord with dorsal and ventral roots attached, demonstrated that the plasticity of PPR could be modulated by repetitive peripheral inputs ( 23 ).
On the other hand, LTP of spinal neurons following a brief C fiber strength conditioning stimulation has been demonstrated in a spinal cord slice ( 2, 18, 31 ). However, to date, there is no investigation using intact spinal preparation to investigate LTP. In the present study, employing an in vivo spinal preparation with intact rootlets attached, we aimed to study whether modifications of PPR plasticity can be induced by tetanic stimulation and the possible neurotransmitters involved in this phenomenon.
METHODS AND MATERIALS
Animal preparations. Adult female Wistar rats weighing 200-300 g were anesthetized with subcutaneous urethane (1.2 g/kg). The animal care and experimental protocol were in accordance with the guidelines of the National Science Council of the Republic of China (NSC 1997). All efforts were made to minimize both animal discomfort and the number of animals used throughout the experiment. The trachea was intubated to keep the airway patent. A PE-50 catheter (Portex, Hythe, Kent, UK) was placed in the left femoral vein for administration of anesthetics when needed. Body temperature was kept at 36.5-37.0°C by an infrared light and was monitored using a rectal thermometer. The rats were monitored for corneal reflex and a response to noxious stimulation to the paw throughout the experiment. If either were present, a supplementary dose (0.4 g/kg iv) of anesthetics was given through the venous catheter. At the end of the experiments, the animals were put down, under deep anesthesia, using an intravenous injection of potassium chloride saturation solution.
Laminectomy. Vertebraes were exposed along the thoracolumbar level, and this was followed by a 4-cm-long laminectomy. A needle (30-gauge, 1.5-cm length) was inserted into the subarachnoid space for intrathecal injection. In some animals, a spinal transection was performed at the level of T13 using a method described elsewhere ( 24 ).
Intraurethral pressure recording. The urinary bladder and the urethra were exposed through a midline incision of the abdomen. The urinary bladder was drained freely into the abdominal cavity by an incision at the bladder dome. A PE-50 catheter was inserted through the opening of the urethra and was connected to a pressure transducer (P23 ID; Gould-Statham). Two 4-0 nylon silk sutures were placed around the bladder trigone and ligated. Intraurethral pressure (IUP) was continuously recorded on an oscilloscope (Tectronics TDS 3014, Wilsonville, OR) through a preamplifier (Grass 7P1, Cleveland, OH).
Nerve dissection. The pelvic nerve was dissected carefully from the surrounding tissue and was then transected as distally as possible by a microscissor. A small branch of the pudendal nerve was dissected from the surface of the urethra for multiple unit recordings. The pudendal nerve was identified by 1 ) anatomic location, 2 ) tonic discharge when saline (0.05-0.10 ml) was infused into the urethra through the urethral catheter, and 3 ) electric stimulation of the pudendal nerve causing an elevation of the IUP. After identification, the pudendal nerve was crushed twice (vertical to each other) as close as possible to the urethra to eliminate afferent firing.
Recording of multiple unit nerve activity. Conventional nerve recording techniques were used for multiple unit recordings from the pudendal nerve efferent fiber as described in a previous report ( 37 ). The firing frequency of each filament was recorded by placing the nerve fiber across a pair of thin bipolar stainless steel wire electrodes. The recorded nerve and the electrodes were bathed in a pool of warm paraffin oil (37°C) to prevent drying. The nerve activity was amplified 20,000-fold and filtered (high-frequency cutoff at 3,000 Hz and low at 30 Hz, respectively) by a preamplifier (Grass P511AC), then continuously displayed on an oscilloscope (Tectronics TDS 3014) and recorded on magnetic tape (Neurocoder, DR-890; Neuro Data). Nerve activities were fed into a window discriminator (WPI, 121, Sarasota, FL) and then integrated and displayed on the recording system (MP30, Biopac, Santa Barbara, CA) ( 22 ).
Recording of electromyogram activity. Epoxy-coated copper wire (50 µm; M.T. Giken, Tokyo, Japan) electromyogram electrodes were placed in the EUS. This was performed using a 30-gauge needle with a hooked electromyogram electrode positioned at the tip. The needle was inserted into the sphincter 1-2 mm lateral to the urethra and then withdrawn, leaving the electromyogram wires embedded in the muscle. EUS electromyogram (EUSE) signals were also amplified and passed through a window discriminator and then recorded on the recording system. The accumulated firing rate during each stimulation was measured ( 4 ).
Experimental arrangement. The schematic arrangement of PEN, EUSE, and IUP, as well as the contralateral pelvic nerve afferent fiber stimulation is shown in Fig. 1. The protocol for assessing the effects of tetanic stimulation of pelvic nerve afferent fiber on PPR activity was as follows. Once the electrode's position was optimized on each nerve, the recording of PEN fiber activity began (referred to as "test activity"). An electric current of square-wave pulses with a pulse duration of 0.1 ms was applied from a stimulator (Grass S88) through a stimulus isolation unit (Grass SIU5B) and a constant current unit (Grass CCU1A). Single shocks at fixed suprathreshold strengths (5-30 V) were repeated at 30-s or 3-min intervals and given through a pair of stimulation electrodes before tetanic stimulation. This frequency of stimulation was chosen for sampling data because it did not result in response facilitation. The intensity of stimulation was gradually increased from 0 to 30 V, and a stimulus intensity that yielded a single spike action potential in the PEN fiber was usually chosen to standardize the baseline PPR activity. After the baseline period, a high-frequency train (3 tetanic stimulations of 1-s duration, each at 100-Hz and 10-s intervals) was delivered at the identical intensity as used for the baseline response.
Fig. 1. Schematic arrangement of pudendal efferent nerve (PEN) and external-urethral sphincter electromyogram (EUSE) recording as well as contralateral pelvic afferent nerve (PAN) fiber stimulation (Stim). The pelvic nerve afferent fiber was stimulated by a pair of stainless steel wire electrodes (indicated by an arrow).
Application of drugs. Drugs were administered by intrathecal injection with a solution of known drug concentrations ( 31 ). Drugs used were 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX; 20 µM, Sigma), D -2-amino-5-phosphonoraleric acid (APV 100 µM, Sigma), bicuculline methiodide (10 µM, Sigma), L -glutamate (0.1 mM, Sigma), and NMDA (0.1 mM, Sigma). Saline, of identical volume to tested agents, was dispensed intrathecally to serve as a vehicle. At the end of the experiment, the location of the injection site was marked by an injection of Alcian blue (0.1-1.5 µl, 2%) in three of the animals, and the animals were then perfused with a solution of 1% paraformaldhyde and 1% glutaraldehyde in phosphate buffer through the ascending aorta. Frozen sections of the spinal cord (56 µm) counterstained with Neutral red were used to verify the location of the injection site and the spread of the dye.
Data analysis. All the data in the text and figures are means ± SE. Statistical analysis of the data was performed by means of ANOVA. For comparisons across treatment groups, a Tukey test was used. A value of <0.05 was accepted as significant.
RESULTS
PPR. Activities recorded from the PEN fiber and EUSE, elicited by low-frequency stimulation (0.033-0.005 Hz) of the pelvic nerve afferent fiber and obtained from one of 25 rats, are shown in Fig. 2. The mean reflex times for pelvic nerve afferent fiber stimulation to evoke an action potential in PEN and EUSE were 25.8 ± 2.3 and 27.3 ± 2.1 ms, respectively ( n = 17).
Fig. 2. Action potentials in PEN and EUSE evoked by a single electric shock on the pelvic afferent nerve fiber (indicated by an arrow at the bottom ).
Tetanization-induced potentiation. The activity of PPR evoked by low-frequency stimulation (0.033-0.005 Hz) varies little over 1 h of testing. In almost one-third of the rats (8 of 25 rats, 32%), the evoked activities of PEN and EUSE remained constant after high-frequency pelvic nerve afferent fiber stimulation (300 pulses at 100 Hz), but about two-thirds of the rats (17 out of 25, 68%) showed a potentiation in PPR. These rats were then used for further study. The responses of PEN and EUSE activities before and after tetanization are shown in Fig. 3, A and B, respectively. Tetanization-induced potentiation of PPR always lasted for the duration of the recording period, which ranged from 30 to 120 min, as long as the stimulation persisted.
Fig. 3. Potentiation of pelvic-to-pudendal reflex activity caused by the tetanization of the pelvic nerve afferent fiber. A and B : PEN and EUSE activities evoked by single electric shocks (indicated by the arrows at the bottom ) before and after the tetanization (Tet; stimulation of 1-s duration each at 100-Hz and 10-s intervals), respectively. Right : activities evoked by the first electric shock in each trace are further investigated using a faster time base. C and D : antagonism of APV (Tet + APV; 100 µM, 2-5 µl bolus) and NBQX (Tet + NBQX; 20 µM, 2-5 µl bolus) on the induction of potentiation of PEN and EUSE activities. APV prevented and NBQX attenuated the induction of potentiation caused by tetanic stimulation.
Effect of spinalization. A spinal transection was performed to rule out the possibility of descending influences from supraspinal structures. In this experiment, in all five rats, the spinal transection showed no effect on tetanization-induced potentiation in PPR.
Antagonism of APV and NBQX. Figure 3 B shows a potentiated PPR induced by tetanic stimulation. The intrathecal application of APV (100 µM, 2-5 µl bolus; C ) ( 31 ), the selective NMDA-receptor antagonist ( 8, 38 ), produced a complete blockage in the potentiation in PPR. On the other hand, NBQX (20 µM, 2-5 µl bolus; D ) ( 31 ), the novel selective non-NMDA-receptor antagonist ( 34 ), caused a partial and reversible antagonism of the potentiation in PPR. Saline (2-5 µl bolus) was also tested via intrathecal injection but showed no effect on the potentiation in PPR. Figure 4 shows the effect of APV and NBQX on the tetanization-induced potentiation in PPR summarized from 17 rats. Because the tendency was parallel and showed no statistical difference between the PEN fiber and EUSE activities, the data were therefore pooled together.
Fig. 4. Summarized data (means ± SE) showing the potentiation (Tet; ) as well as antagonism of APV (Tet + APV; ) and NBQX (Tet + NBQX; ) for 17 rats following the tetanic stimulation. ** P < 0.01, n = 17.
Agonist-induced potentiation. In 10 rats, intrathecal glutamate (0.1 mM, 2-5 µl) produced a potentiation in PPR ( Fig. 5 C ). As shown in Fig. 5 D, NMDA (0.1 mM, 2-5 µl) could also elicit potentiation repeatedly in the same preparation, but saline of identical volume caused no response. The effect of tetanization of the pelvic nerve afferent fiber, intrathecal glutamate, and NMDA on PPR, summarized from 10 rats, is shown in Fig. 6. Electric stimulation in the presence of a chemical agonist was not required for potentiation. Furthermore, the agonist-induced potentiation was shorter compared with the high-frequency tetanus-induced potentiation, i.e., the firing frequency of glutamate and NMDA-induced potentiation decreased from 49.3 ± 14.6 and 19.7 ± 2.0 Hz at the beginning (1 s) to 20.3 ± 4.7 and 10.0 ± 7.1 Hz, respectively, at the end of the experiment (30 min), whereas the tetanization-induced potentiation remained unchanged (from 34.8 ± 9.4 to 32.1 ± 9.5 Hz).
Fig. 5. Glutamate (0.1 mM, 2-5 µl) and NMDA (0.1 mM, 2-5 µl) mediated potentiation in pelvic to pudendal reflex. A : PEN and EUSE activities evoked by single electrical shocks (indicated by the arrows at the bottom ) before tetanization. B - D : tetanic pelvic nerve afferent fiber stimulation (Tet; B ), a bolus of glutamate (Glu; C ), and NMDA ( D ) were given, respectively. After each treatment, the evoked activity in PEN and EUSE was potentiated. Right : activities evoked by the first electrical shock in each trace are further investigated using a faster time base.
Fig. 6. Summarized data (means ± SE) showing the potentiation in pelvic to pudendal reflex activity induced by intrathecal glutamate ( ), NMDA ( ), and tetanization ( ) of pelvic nerve afferent fiber. ** P < 0.01, n = 10.
Effects of GABA A blockage. The induction of potentiation in PPR (mean firing frequency 34.8 ± 9.4 Hz) was not abolished by the intrathecal administration of the GABA A ergic receptor antagonist bicuculline (10 µM, 2-5 µl, 32.6 ± 9.6 Hz, P = not significant).
Secondary changes in response to plasticity. As shown in Fig. 7 A, a PPR was induced by a "test stimulation" (0.033-0.005 Hz) and a contraction wave in IUP was produced by urethral sphincter contraction. After the tetanic stimulation, as shown in Fig. 7 B, firing in PEN and EUSE, evoked by each stimulation, increased. Furthermore, the duration of the contraction wave of IUP, secondary to the urethral sphincter contraction, increased in a parallel fashion, although the peak pressure remained unchanged. The time relationships among activities of PEN, EUSE, and IUP waves were further investigated using a faster time base ( Fig. 7, A and B, right ). After the main IUP contraction wave, potentiated PPR produced successive contractions of smaller amplitude ( Fig. 7 B ), compared with that induced by test stimulation ( Fig. 7 A ). Furthermore, each contraction shows a close time relationship to the firing of the pudendal nerve efferent fiber and EUSE resulting from potentiation in PPR.
Fig. 7. Changes in intraurethral pressure (IUP) resulting from potentiated pelvic to pudendal reflex. A : PEN, EUSE, and IUP activities before tetanization. B : increase in the duration of contraction wave of the IUP was induced after tetanic stimulation (Tet). Right : activities evoked by the first electrical shock in each trace are further investigated using a faster time base. The duration of the IUP wave was elongated, and several successive contractions of small amplitude were elicited by the potentiated activities in PEN and EUSE.
DISCUSSION
In a variety of brain structures, repetitive activation of synaptic connections can lead to modulation of synaptic transmission ( 19, 26, 35 ). Two types of afferent-induced excitability changes have been described in vitro. The first is the phenomenon of windup, where repetitive stimulation progressively increases synaptic efficacy in spinal dorsal horn neurons (6, 25, 32, 40, 42). The second is the LTP, which is characterized as a prolonged increase in the excitability of spinal neurons following a brief C fiber strength conditioning stimulation ( 2, 18, 31 ). The mechanism of LTP is of particular interest, for this phenomenon exhibits a characteristic postulated as a requirement for memory and learning ( 13, 17, 28 ). The presence of the LTP in spinal cord preparations has been reported using spinal preparations ( 2, 18, 31, 33 ). However, because of the limitations in the brain slice technique, the analysis of afferent fibers, essential for inducing LTP as well as the destination and physiological relevance of this potentiation, remains unclear. In the present study, using an in vivo spinal cord preparation having intact dorsal and ventral roots attached, the afferent and efferent arms involved in a potentiated reflex can be investigated. The major finding in this study is that brief C fiber tetanization of the pelvic nerve afferent fiber also results in a substantial increase in the strength of PPR; similarly, potentiation in reflex is able to elicit secondary elongation in the duration of urethral sphincter contraction, therefore increasing the resistance of the lower urinary tract.
Physiological and pathological relevance. PPR is physiologically important in urine continence during the storage phase of voiding cycles ( 10 ). A recent study on the windup phenomenon demonstrated that repetitive pelvic afferent stimulation resulted in a substantial increase in the strength of PPR activity and the physiological response secondary to this reflex. These results suggest that during the storage phase, repetitive discharges in pelvic afferent inputs caused by volume distension may induce prolonged urethral sphincter contraction. The resistance in the urethra, which resulted from sphincter contraction, is essential for urine continence in the physiological condition ( 23 ). On the other hand, Randi et al. ( 32 ) suggested that tetanization-induced enhancement of excitatory postsynaptic potential may be related to the mechanism involved in the generation of postinjury pain hypersensitivity. Chemical irritation-induced hyperactivity in the urethral sphincter was also reported by investigators ( 3, 36 ). High resistance in the lower urinary tract as a result of a hyperactive sphincter is suggested to cause obstructive bladder dysfunctions.
In the present study, tetanic stimulation was used to induce potentiation in PPR. Because the entire pelvic nerve trunk was stimulated with suprathreshold intensity, i.e., C fibers were recruited, the PPR plasticity in the present study may be involved in pathological conditions, such as hyperactive bladder caused by inflammation that can sensitize C fiber afferents. Potentiated PPR elicited by such pathological conditions, in turn, may cause a high urethral resistance that induces obstructive bladder dysfunctions.
Possible neurotransmitters involved. The induction of LTP is presently thought to require both activation of NMDA and AMPA receptors by synaptically released glutamate ( 5, 9 ) and depolarization of the postsynaptic membrane ( 14 ). Moreover, studies of LTP in the hippocampus revealed that although LTP is induced postsynaptically, the maintenance of LTP may be, at least in part, presynaptic due to long-lasting enhancement of transmitter release ( 9, 10, 20, 27 ). In the present study, intrathecal application of NMDA and AMPA receptor antagonists blocked or attenuated the potentiation in PPR, suggesting a close connection to the mechanism of LTP in the lower spinal cord. This conjecture is in accordance with the report of Randi et al. ( 31 ) that suggests LTP can be induced in spinal dorsal horn neurons. However, for the nature of multiple units recording technique is highly variable, whether NBQX attenuated PPR (as shown in Fig. 3 ) needs further investigations. On the other hand, in this study, the enhancement of reflex activities in PEN and EUSE was induced by tetanic stimulation. Further investigation of the synaptic efficacy on the dorsal horn, within the spinal cord, needs to be elucidated as to whether this enhancement is mediated by a "LTP-like" synaptic transmission. On the other hand, it is well known that pelvic afferent nerve stimulation or bladder distension can also elicit the pelvic-to-hypogastric nerve reflex ( 10 ), which induces contraction of the internal urethral sphincter and, in turn, increases the IUP. This possibility cannot be ruled out.
Although there is little to suggest that inhibitory mechanisms contribute to the maintenance of synaptic LTP ( 15 ), there is evidence that its induction is affected by inhibitory influences ( 11, 12, 39 ). It is known that the cell remains depolarized for a sufficient time to enable the activation of the NMDA receptor during high-frequency stimulation. This is made possible, at least in part, by the frequency-dependent depression of synaptic inhibition caused by GABA A, feeding back and depressing its own release by action on the presynaptic GABA A receptors ( 7 ). The latter finding demonstrated a role for the GABA A receptor on synaptic plasticity ( 5 ). In this study, potentiation in PPR induced by tetanic stimulation was not affected by intrathecal application of bicuculline, a GABA A -receptor antagonist, ruling out the involvement of the GABA A polysynaptic inhibitory pathway. However, the role of other inhibitory pathways, such as GABA B, serotonin, and glycine, should be investigated in further studies.
GRANTS
This research was supported by the National Science Council of the Republic of China (NSC 91-2320-B-040-050 and 92-2320-B-040-036 to T.-B. Lin).
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作者单位：Department of Physiology, College of Medicine, Chung-Shan Medical University, Taichung, Taiwan 10018