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Vol. 285, Issue 1, 22-27, April 1998
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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This study was undertaken to evaluate the role of glutamate receptors
at spinal synapses on the ascending limb of the micturition reflex. In
urethane-anesthetized female rats, a tungsten electrode was inserted
stereotaxically into the dorsal part of the rostral pons to record
field potentials which were evoked by electrical stimulation of the
pelvic nerve (PLN) (1-15 V, 0.05 ms pulse duration at 100-300 Hz,
5-30 ms train duration). The effects of glutamate receptor antagonists
administered intrathecally (i.t.) on the PLN-evoked field potentials in
the dorsal part of the rostral brainstem were examined. PLN stimulation
evoked short latency (10-22 ms) negative field potentials (85 ± 4 µV) in a limited area of the dorsal part of the rostral pons
(bregma 
9.0 to 8.4, L 0.5 to 1.5, H 4.2 to 5.4). The i.t.
administration of LY215490 (0.1-30 µg), a competitive
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
antagonist, reduced the amplitude of the evoked potentials in a
dose-dependent manner; 84 ± 6%, 59 ± 11% (P < .001), 31 ± 10% (P < .001), 17 ± 9% (P < .001) of control after 0.1, 1, 10, 30 µg of LY215490, respectively.
The i.t. administration of MK-801 (1-100 µg), a noncompetitive
N-methyl-D-aspartate (NMDA) receptor antagonist, also
reduced the amplitude of the evoked potentials in a dose-dependent
manner; 93 ± 21%, 76 ± 14%, 52 ± 9% (P < .001), 39 ± 9% (P < .001) of control after 1, 10, 30, 100 µg of MK-801, respectively. Combined administration of LY215490 (0.1 µg) and MK-801 (1 µg), in doses which individually did not elicit a
significant effect, markedly reduced the amplitude of the evoked
potentials (27 ± 9% of control, P = .0002). These results suggest that AMPA and NMDA glutamatergic synaptic mechanisms play a key
role in the spinal processing of afferent input from the bladder and
that these mechanisms function synergistically in the ascending limb of
the spinobulbospinal micturition reflex pathway.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Micturition
is mediated by a spinobulbospinal reflex pathway consisting of: (1) an
ascending limb from the lumbosacral spinal cord, (2) an integration
center in the rostral brainstem known as the PMC and (3) a descending
limb from the PMC back to the parasympathetic nucleus in the
lumbosacral spinal cord (Kuru, 1965
; Mallory et al., 1989;
Noto et al., 1991; de Groat et al., 1993).
Previous pharmacological studies revealed that glutamic acid plays an
important role in the reflex pathways controlling the lower urinary
tract. Administration of NMDA receptor antagonists (MK-801 or LY274614)
or AMPA/kainate receptor antagonists (GYKI 52466 or LY215490) to
urethane-anesthetized rats depressed the amplitude of reflex bladder
contractions evoked by bladder distension (Maggi et al.,
1990; Yoshiyama et al, 1991, 1993a, b, 1995a; Kakizaki et al, 1996) or by electrical stimulation of the PMC
(Matsumoto et al., 1995a, b). Further, microinjection of
glutamate or related excitatory amino acids into the PMC or adjacent
areas facilitated micturition in the rat and cat (Willette et
al, 1988; Mallory et al., 1991). These data indicate
that glutamatergic mechanisms play a pivotal role at synapses in the
PMC and in the descending limb of the micturition reflex pathway.
However, a possible role of glutamate in the ascending limb of the
micturition reflex pathway has not been examined.
In the present study electrophysiological techniques were used to
evaluate the contribution of spinal NMDA and AMPA glutamatergic mechanisms to the ascending limb of the micturition reflex pathway in
the rat. Previous studies revealed that glutamatergic mechanisms are
involved in spinal nociceptive and non-nociceptive transmission (Dougherty et al., 1992; Coderre, 1993; Cumberbatch et
al., 1994; Birder and de Groat, 1992; Kakizaki et al.,
1996). In addition, synergistic interactions between NMDA and AMPA
glutamate receptors have been detected in the spinal processing of
nociceptive input from the lower urinary tract (Kakizaki et
al., 1996). Possible interactions between these two types of
glutamate receptors in the ascending limb of the micturition reflex
pathway were also examined in this study.
Preliminary accounts of these findings have appeared in an abstract
(Kakizaki et al., 1997).
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animal preparation. Experiments were performed on 20 female Wistar rats weighing 265 to 320 g (mean-286 g). The animals were anesthetized with a subcutaneous injection of urethane (1.2 g/kg), and cannulae (PE-50) were placed in the carotid artery for monitoring blood pressure and in the external jugular vein for intravenous drug administration. A tracheostomy tube (PE-240) was inserted to facilitate respiration and permit artificial ventilation after neuromuscular blockade.
An i.t. catheter was inserted with a modification of the technique described by Yaksh and Rudy (1976). The atlanto-occipital membrane was
incised at the midline with the tip of an 18-gauge needle. A catheter
(PE-10), which was filled with artificial CSF (Feldberg and
Fleischhauer, 1960), was inserted through the slit into the
subarachnoid space and advanced caudally to the
L6-S1 level of the spinal cord. The volume of
fluid within the catheter was kept constant at 10 µl for all
experiments by adjusting the length of the tubing precisely (16 cm). At
the end of experiment, a laminectomy was performed to verify the
position of the catheter tip.
Through a mid-line abdominal incision, the PLN was isolated and
prepared for stimulation. To prevent the bladder from filling with
urine during the experiment, both ureters were tied distally, cut and
the proximal ends cannulated (PE-10) and drained externally. The
urinary bladder was cannulated by passing a catheter (PE-90) through
the external urethral orifice. The catheter was secured in place by a
ligature around the urethral orifice and connected to a pressure
transducer to monitor intravesical pressure.
The rat was placed in a stereotaxic apparatus and a small craniotomy
was performed to insert a recording electrode into the dorsal pontine
tegmentum. After completion of the surgical procedures, the animal's
body was rotated 120° to expose the urinary bladder and PLN.
Abdominal skin flaps were tied to a metal frame to form a cavity that
was filled with warm mineral oil. The PLN was placed on bipolar silver
electrodes for stimulation. A fine monopolar tungsten electrode
(diameter, 10-20 µm), insulated with Teflon except for the tip, was
used for recording in the brainstem. Animals were paralyzed with
-bungarotoxin (0.4 mg/kg i.v.), a noncompetitive blocker of striated
muscle nicotinic receptors, and artificially ventilated. This agent has
a long duration of action which allowed one dose to produce complete
neuromuscular blockade throughout the experiment (3-6 hr)
(Chiappinelli, 1985).
Initially, the bladder was filled slowly with saline (0.04 ml/min) to
confirm the presence of reflex bladder contractions. Then the bladder
was emptied through the urethral catheter. A recording electrode was
introduced stereotaxically into the medial part of the dorsal pontine
tegmentum in 0.25- or 0.5-mm steps. Sites in the pons were identified
where pelvic afferent stimulation (1-15 V, 0.05 ms pulse duration at
100-300 Hz, 5-30 ms train duration) evoked field potentials. These
stimulus parameters were based on a previous report (Noto et
al., 1991). Neural activity was displayed on an oscilloscope, and
10 successive evoked potentials were averaged with a digital computer
and plotted on a plotter. The latency measurements were made from
computer-averaged evoked potentials. The latencies were measured from
the stimulus artifact to the peak amplitude of the evoked potentials.
Stimulation parameters were varied to evoke a response of maximal
amplitude and shortest measurable latency. Recording sites were
identified by stereotaxic coordinates. Histological confirmation of the
location of the tip of the recording electrode was not performed in
this study.
Glutamate antagonists were administered i.t.. Before drug
administration, control injections (10 µl) of artificial CSF were tested to evaluate possible injection artifacts. Drug solution was
injected slowly for a period of 30 sec to 1 min to minimize volume
effects. Cumulative drug dose-response curves were obtained by giving
i.t. injections of LY215490, a selective, competitive AMPA receptor
antagonist (Ornstein et al., 1993a, b; Gill and Lodge, 1994;
Schoepp et al., 1995) or MK-801, a noncompetitive NMDA
receptor antagonist, every 15 min. In this study, cumulative doses of
LY215490 and MK-801 injected i.t. were 0.1, 1, 10 and 30 µg and 1, 10, 30 and 100 µg, respectively. To accomplish sequential administrations of several concentrations of drugs, the intrathecal catheter, which was initially filled with 10 µl of artificial CSF
(vehicle), was flushed sequentially with the following volumes of drugs
and vehicle; LY215490: (1) 10 µl of 0.01 µg/µl solution; (2) 9 µl of 0.1 µg/µl solution and 1 µl of vehicle; (3) 9 µl of 1 µg/µl solution and 1 µl of vehicle; (4) 10 µl of 10 µg/µl
solution; and (5) 2 µl of 10 µg/µl solution; MK-801: (1) 10 µl
of 0.1 µg/µl solution, (2) 9 µl of 1 µg/µl solution and 1 µl of vehicle, (3) 10 µl of 10 µg/µl solution, (4) 2 µl of 10 µg/µl solution, and (5) 7 µl of 10 µg/µl solution. These
doses were chosen based on the results of pilot experiments
(n = 5) as well as previous experiments (Yoshiyama
et al., 1997).
Evaluation and statistical analysis. The effects of drugs on the latency and amplitude at the peak of the evoked potentials were evaluated 10 min after each dose. Latency to peak rather than to the onset of the evoked potentials was used because it exhibited greater stability during the experiment. All values in the text are expressed as mean ± S.E.M. The changes in the peak amplitude of the evoked responses after drug treatments were evaluated statistically with repeated measures analysis of variance (ANOVA) followed by Tukey-Kramer test as a post hoc multiple comparison procedure. For all statistical tests, P < .05 was considered significant.
Drugs.
Drugs used in this study include: -bungarotoxin
(Sigma Chemical Co., St. Louis, MO), LY215490
[(3SR,4aRS,6RS,8aRS)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid, Lilly Research Laboratories, Indianapolis, IN], MK-801
(dizocilpine, Merck, Sharp & Dohme Research Laboratories, West Point,
PA). LY215490 and MK-801 were dissolved in artificial CSF and these
solutions were then adjusted to pH 7.2 to 7.4. -Bungarotoxin was
dissolved in saline.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Evoked responses in the dorsal part of the rostral pons after PLN
stimulation.
PLN stimulation evoked short latency (10-22 ms)
negative field potentials (85 ± 4 µV) in a relatively
limited area of the PAG (bregma 9.0 to 8.4, L 0.5 to 1.5, H 4.2 to
5.4). The threshold intensity of PLN stimulation ranged from 1 to 4 V
in different animals. The latency from the onset of stimulation to the
peak of the evoked potentials was 37.4 ± 1.8 ms. In preliminary
experiments (n = 3), repeated injections of 10 µl of
artificial CSF (up to five or six times, every 15 min) did not change
the latency and amplitude of the evoked potentials.
Effects of AMPA receptor antagonist (LY215490) on the evoked response elicited by PLN stimulation. Intrathecal injection of vehicle (artificial CSF) did not have any effect on the evoked potentials. Cumulative doses of LY215490 (0.1, 1, 10 and 30 µg) were injected i.t. every 15 min (n = 5). Intrathecal injection of LY215490 reduced the amplitude of the evoked potentials in a dose-dependent manner (fig. 1): 84 ± 6%, 59 ± 11% (P < .001), 31 ± 10% (P < .001) and 17 ± 9% (P < .001) of control after 0.1, 1, 10 and 30 µg of LY215490, respectively. The evoked responses did not recover during the 4-hr period after the highest dose of LY215490. The drug did not change the latency of the evoked potentials (table 1).
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Effects of NMDA receptor antagonist (MK-801) on the evoked responses elicited by PLN stimulation. Cumulative doses of MK-801 injected i.t. every 15 min (n = 5) reduced the amplitude of the evoked potentials in a dose-dependent manner (fig. 2). The potentials were reduced to 93 ± 21%, 76 ± 14%, 52 ± 9% (P < .001) and 39 ± 9% (P < .001) of control after 1, 10, 30 and 100 µg of MK-801, respectively. The evoked responses did not recover during the 4-hr period after the highest dose of MK-801. The latency of the evoked potentials was not altered by MK-801 (table 1).
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Effects of combined administration of MK-801 (1 µg) and LY215490 (0.1 µg) on the potentials evoked by PLN stimulation. Combined i.t. administration of MK-801 and LY215490 was examined in five rats by injecting one of the drugs and then 15 min later injecting the second drug. Combined administration of 1 µg of MK-801 and 0.1 µg of LY215490, which individually did not have a significant effect on the amplitude of the evoked potentials (figs.1 and 2), significantly reduced (to 27% of control, P = .0002) the amplitude of the evoked potentials (fig. 3). Combined administration of MK-801 and LY215490 did not change the latency of the evoked potentials (table 1).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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This study revealed that both AMPA and NMDA glutamatergic transmission plays a key role in the spinal processing of afferent input from the bladder and that spinal NMDA and AMPA glutamatergic synaptic mechanisms interact synergistically in the ascending limb of the spinobulbospinal micturition reflex pathway.
In the present study, short latency (10-22 ms) field potentials were
evoked by PLN stimulation in a relatively limited area of the PAG.
These findings confirm the results of a previous study which showed
that short latency (13 ± 3 ms) field potentials were elicited by
PLN stimulation in the PAG (Noto et al., 1991). Because the
latency for PLN to the PAG potentials was shorter than the latency for
PLN to the PMC potentials (Noto et al, 1991), it was suggested that the PAG might function as the receiving area for the
ascending limb of the micturition reflex pathway and that neurons in
the PAG might relay information to neurons in the PMC which then
provide an input back to the sacral parasympathetic nucleus.
Further support for this concept has been obtained in axonal
tracing studies in the cat (Blok and Holstege, 1994; Blok et
al, 1995; VanderHorst et al, 1996).
Intrathecal injection of an AMPA or NMDA antagonist reduced the
amplitude of the evoked potentials in a dose-dependent fashion (figs. 1
and 2). Glutamate is present in both primary afferent pathways as well
as in interneurons of the dorsal horn (Cotman et al., 1987;
Wanaka et al., 1987; Westlund et al., 1990; Araki and de Groat, 1996). Thus glutamate receptor antagonists injected i.t.
might act at several sites. For example, they might reduce the synaptic
transmission from primary afferent fibers to interneurons or spinal
tract neurons, or depress interneuronal transmission.
Previous studies have shown that c-fos expression, a
functional marker for nociceptive pathways in CNS, was increased in the spinal cord after chemical irritation of the lower urinary tract and
that AMPA and NMDA antagonists (LY215490 and MK-801, respectively) reduced the c-fos expression in all of the relevant areas of
the spinal cord, including dorsal horn, dorsal commissure and lateral laminae V-VII (Birder and de Groat, 1992; Kakizaki et al.,
1996). These observations are consistent with the present findings;
together they provide strong support for the view that glutamatergic
synapses are essential for the spinal processing of nociceptive and
non-nociceptive afferent input from the bladder.
In the present study, LY215490 was used as an AMPA receptor antagonist.
Previous in vivo and in vitro studies indicate
that this drug is a potent, competitive antagonist at AMPA receptors. In vitro binding studies indicate that this agent acts as a
competitive antagonist at AMPA receptors with an
IC50 of 1.8 to 4.8, but at a 10-fold higher
concentration it can also act as an antagonist at NMDA receptors
(Schoepp et al., 1996). In vivo at doses between 25 and 75 mg/kg i.p. LY215490 elicited a selective antagonism of the
neurotoxic effect of AMPA in the rat striatum, without affecting the
neurotoxicity to NMDA (Schoepp et al., 1996). In the mouse,
even much larger doses (up to 320 mg/kg i.p.) did not alter NMDA
toxicity (Ornstein et al., 1993a, b). However, a concern in
interpreting the present data is whether the doses of LY215490 administered i.t. act selectively on AMPA receptors or whether they
also have some effect on NMDA receptors. Indirect evidence suggests
that the effects of at least the low doses of the drug (0.1 and 1 µg)
on the ascending limb of the micturition reflex are caused by block of
AMPA receptors. For example, it is clear from other studies in
vivo and in vitro that the micturition reflex depends
on AMPA glutamatergic mechanisms as evidenced by block of AMPA
receptors with various drugs (CNQX, GYKI52466) (Matsumoto et
al., 1991; Sugaya and de Groat, 1994; Araki and de Groat, 1996; Yoshiyama et al., 1995a) and that NMDA mechanisms also play
an important role (Maggi et al., 1990; Yoshiyama et
al., 1991, 1993a, b). However, under certain conditions such as
the decerebrate unanesthetized rat, AMPA mechanisms play an essential
role and NMDA mechanisms are not required. In these animals low doses
of LY215490 administered i.v. (1-10 mg/kg) or i.t. (0.1-10 µg)
depressed the micturition reflex (Yoshiyama et al, 1997);
whereas even large doses of MK-801 (up to 30 mg/kg i.v.) did not induce
a detectable block (Yoshiyama et al., 1994). These data
indicate that the lower doses (0.1-1 µg) of LY215490 used in the
present experiments acted selectively on AMPA receptors in the spinal
cord. However, it is impossible to determine whether the higher doses
of the drug (10-30 µg i.t.) acted selectively or whether the effects
of these doses were caused by a combined block of both types of
glutamatergic receptors.
Combined administration of low doses of AMPA and NMDA antagonists,
which individually did not have a significant effect on PLN-evoked
potentials, dramatically reduced the amplitude of the evoked potentials
(mean decrease-73%). This result indicates that fast (AMPA) and slow
(NMDA) types of glutamatergic transmission interact synergistically in
the spinal processing of afferent input from the bladder. Synergistic
interactions between AMPA and NMDA glutamate receptor antagonists to
depress spinal c-fos expression after lower urinary tract
irritation also have been demonstrated previously (Kakizaki et
al., 1996). This synergism is attributable to the action of
AMPA/kainate receptors to induce synaptic depolarization, which
facilitates the opening of NMDA receptor channels (Collingridge and
Lester, 1989). Membrane depolarization removes the voltage-dependent
blockade of the NMDA receptor by Mg++ (MacDonald
and Nowak, 1990) and thereby enhances NMDA receptor-mediated transmission. This unblocking of NMDA receptor channels is likely to
occur during high levels of afferent input induced by bladder distension or electrical stimulation of afferent fibers in PLN that
would release glutamate as well as other transmitters at spinal
synapses. Thus synergistic interactions between AMPA and NMDA synaptic
mechanisms seem to be necessary for optimal transmission of afferent
information from the bladder to the PMC. Consequently, combinations of
AMPA and NMDA receptor antagonists produce a more dramatic depressant
effect than administration of individual antagonists.
Previous studies of somatic sensory pathways have indicated that
non-NMDA receptors mediate monosynaptic activation of dorsal horn
neurons by primary afferent fibers, whereas NMDA receptors mediate
polysynaptic inputs to the dorsal horn (Davies and Watkins, 1983;
Schouenborg and Sjolund, 1986; Evans and Long, 1989; Morris, 1989;
Dickenson and Sullivan, 1990). A similar organization of glutamatergic
mechanisms has been described in the afferent pathways to primate
spinothalamic tract neurons (Dougherty et al., 1992) and may
be important in processing afferent input from the bladder.
In this study, i.t. injection was used to deliver drugs exclusively to
the spinal cord. A previous study showed that 15 min after i.t.
injection of 10 µl of dye (1% methylene blue) at the caudal lumbar
level, the dye was distributed to the
T9-S4 level of the spinal
cord (Igawa et al., 1993). Thus in the present experiments there was sufficient time for drugs administered at the
L6-S1 level to have acted
at other levels of the neuraxis. However, because afferent pathways in
the PLN project almost exclusively to
L6-S1 (de Groat et
al., 1993) and because these segments are important for spinal
processing of afferent input from the bladder (Birder and de Groat,
1993), it is unlikely that the spread of drugs beyond the
L6-S1 level of the spinal
cord would have prominent qualitative influence on the results of this
study. This conclusion is supported further by the finding that
injections of LY215490 at rostral levels of the spinal cord
(C2) elicited a very delayed (75 min) and weak
depression of bladder reflexes (Yoshiyama et al., 1997),
whereas injections at L6-S1
produced a rapid onset and complete block of reflexes.
Previous pharmacological studies have revealed that administration of
NMDA receptor antagonists (MK-801 or LY274614) or AMPA/kainate receptor
antagonists (GYKI 52466 or LY215490) to the urethane-anesthetized rats
depressed the amplitude of reflex bladder contractions evoked by
bladder distension (Maggi et al., 1990; Yoshiyama et
al, 1991, 1993a, b, 1995a) or by electrical stimulation of the PMC
(Matsumoto et al., 1995a, b). Synergistic depressant effects
of AMPA and NMDA glutamate receptor antagonists on the amplitude of
reflex bladder contractions also have been detected in unanesthetized decerebrate rats (Yoshiyama et al, 1995b, 1997).
Patch-clamp studies in the neonatal rat spinal slice preparation
indicate that AMPA and NMDA glutamate receptors are important in the
mediation of fast and slow transmission, respectively, between
excitatory interneurons and preganglionic neurons in the lumbosacral
parasympathetic nucleus (Araki and de Groat, 1996) These data indicate
that glutamatergic transmission plays a crucial role in the function of
the descending or efferent component of the micturition reflex pathway.
This study provides evidence that spinal glutamatergic transmission also plays a pivotal role in the ascending limb of the micturition reflex pathway. Thus, glutamate receptors at spinal synapses on both
ascending and descending limbs of the micturition reflex pathway are
important for the control of micturition.
In summary, the results of this and previous studies indicate that glutamate is an important neurotransmitter in the micturition reflex pathway in the rat. The spinal processing of afferent input from the urinary bladder depends on transmission mediated by both AMPA and NMDA receptors. In addition, a synergistic interaction between AMPA and NMDA transmission appears to be important in the ascending limb of the spinobulbospinal micturition reflex pathway.
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Acknowledgments |
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The authors are grateful to Eli Lilly and company, and Merck, Sharp & Dohme Research Laboratories for gifts of LY215490 and MK-801, respectively.
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Footnotes |
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Accepted for publication November 28, 1997.
Received for publication April 24, 1997.
1 This work was supported by National Institutes of Health Grants DK-49430 (W.D.) and DK-51402 (W.D.).
2 Present address: Department of Urology, Hokkaido University School of Medicine, Sapporo, 060 Japan.
Send reprint requests to: William C. de Groat, Ph.D., Department of Pharmacology, University of Pittsburgh School of Medicine, W1357 Biomedical Science Tower, Pittsburgh, PA 15261.
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Abbreviations |
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AMPA, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid;
NMDA, N-methyl-D-aspartate;
PMC, pontine micturition center;
CSF, cerebrospinal fluid;
PLN, pelvic nerve;
PAG, periaqueductal gray;
CNS, central nervous system;
i.t., intrathecal.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, on the micturition reflex in the rat.
J Pharmacol Exp Ther
280:
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