Vol. 283, Issue 3, R576-R582, September 2002
NK1 receptor and its interaction with NMDA receptor
in spinal c-fos expression after lower urinary tract
irritation
Takahiko
Mitsui1,
Hidehiro
Kakizaki1,
Shinobu
Matsuura1,
Hiroshi
Tanaka1,
Kaname
Ameda1,
Mitsuhiro
Yoshioka2, and
Tomohiko
Koyanagi1
1 Department of Urology and
2 Department of Pharmacology, Hokkaido University
Graduate School of Medicine, Sapporo, 060 - 8638, Japan
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ABSTRACT |
The role of neurokinin 1 (NK1) receptor and possible interaction between
NK1 and N-methyl-D-aspartic acid
(NMDA) glutamatergic receptors were investigated on spinal
c-fos expression after lower urinary tract irritation with
acetic acid infusion in rats. At both levels of the first
(L1) and sixth lumbar (L6) spinal cord, where most of hypogastric nerve and pelvic nerve afferent terminals project, respectively, the selective NK1 receptor
antagonist CP-99,994 dose dependently reduced the total number of
c-fos protein (Fos)-positive cells. However, CP-100,263, the
enantiomer of CP-99,994 with a very low affinity for NK1
receptor, did not have any effect on the total number of Fos-positive
cells. Coadministration of a low dose (1 mg/kg) of CP-99,994 and NMDA
receptor antagonist (MK-801), either of which alone did not affect
c-fos expression, significantly inhibited c-fos
expression at both levels of the spinal cord. Regarding regional
differences, the number of Fos-positive cells decreased significantly
at all regions of the L6 level, but only at the dorsal horn
of the L1 level. These results indicate that NK1 receptor is involved in spinal c-fos
expression after lower urinary tract irritation and that
NK1 and NMDA receptors have a synergistic interaction in
the spinal processing of nociceptive input from the lower urinary tract.
CP-99,994; nociception; bladder; acetic acid; spinal cord
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INTRODUCTION |
THE
TACHYKININ neurokinin 1 (NK1) receptor is
widely distributed in both the central and peripheral nervous system.
At the spinal cord level, NK1 receptors are activated
during the synaptic transmission, especially in response to noxious
stimuli applied at the receptive field of primary afferent neurons
(30). Neurons in lamina I of the spinal cord expressing
NK1 receptor are reported to encode for the intensity of
noxious stimulation (13). There have been many studies
that examined the role of substance P and NK1 receptors in
visceral pain because substance P is expressed by a much greater
proportion of visceral than cutaneous or muscle afferents
(29). Chemical irritation of the urinary bladder with formalin in rats induced c-fos expression in more than 80%
of substance P receptor-like immunoreactive neurons of the lumbosacral (L-S) spinal cord (20). NK1 antagonists
inhibited nociceptive responses to visceral stimulation (22,
28). Moreover, NK1 knockout mice showed profound
deficits in behavioral responses to visceral chemical stimulation
(intracolonic capsaicin) and to cyclophosphamide-induced cystitis
(17). Thus there is considerable evidence implicating a
critical role of substance P and NK1 receptor in visceral pain.
On the other hand, N-methyl-D-aspartic acid
(NMDA) glutamatergic receptor is also involved in somatic as well as
visceral nociception (7-9, 24, 32). Recent studies
have suggested that the excitatory amino acid (EAA) glutamate interacts
with substance P-containing sensory afferents to modulate nociceptive transmission. Substance P and glutamate have been found to coexist in
primary afferents (12), and presynaptic NMDA autoreceptors were detected near the neurotransmitter release sites in primary afferents (19). Presynaptic NMDA receptors that were
located on substance P-containing primary afferents facilitated
nociception through a release of substance P (11, 18, 21).
Coadministration of a low dose of NMDA receptor antagonist and
NK1 receptor antagonist markedly reduced NMDA
receptor-mediated responses such as facilitated flexor reflex
(36). Chapman and associates (6) showed that NK1 and NMDA receptor interactions contributed to spinal
c-fos expression after intraplantar injection of formalin in
rats. Taken together, these findings suggest interaction between
NK1 and NMDA receptors in somatic nociception. However,
there are few in vivo studies investigating the possible interaction of
both receptors in visceral nociception, especially in bladder nociception.
Chemical irritation of the bladder has been used for producing noxious
stimulation of the bladder. Intravesical instillation of acetic acid is
known to increase spinal c-fos expression (1-4, 14, 15, 25). Previous studies have shown that NMDA receptors have a critical role in spinal c-fos expression after lower
urinary tract irritation (1, 16). However, neither the
precise role of NK1 receptor nor the possible interaction
between NK1 and NMDA receptors has been examined in spinal
c-fos expression after lower urinary tract irritation.
In the present study, the selective NK1 receptor antagonist
CP-99,994 (23, 33) was used to examine the role of
NK1 receptor in spinal c-fos expression after
lower urinary tract irritation. Then the effects of coadministration of
a low dose of CP-99,994 and the NMDA receptor antagonist MK-801
(1-3, 16) were examined in the same model to evaluate
the interaction between the two receptors in spinal nociceptive processing.
A preliminary report of these investigations was presented in abstract
form (27).
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METHODS |
Adult female Wistar rats weighing between 160 and 220 g
were used in the present study. All experimental procedures were
performed in accordance with the Guideline for the Care and Use of
Laboratory Animals by the Animal Research Committee of Hokkaido
University Graduate School of Medicine. The work presented here fully
conforms with the American Physiological Society's "Guiding
Principles for Research Involving Animals and Human Beings."
In urethane-anesthetized (1.2 g/kg ip injection) rats, tracheal
intubation was performed to facilitate respiration. A cannula (PE-50)
was inserted in the right external jugular vein for intravenous drug
administration. The urinary bladder was exposed through a lower midline
abdominal incision, and 1% acetic acid in saline was infused (0.12 ml/min) for 2 h via a needle (23 gauge), which was inserted
through the bladder dome just before the start of acetic acid infusion.
Two-hour infusion time was adopted in this study according to the time
course of c-fos expression after bladder irritation
(2). Because the urethra remained open, fluid that was
infused into the bladder could be expelled or leak out during the
continuous infusion. To eliminate the possibility of irritation of the
perineal skin and vaginal mucosa, mineral oil was applied to the area
around the urethral meatus.
The effects of intravenous administration of CP-99,994 (Pfizer, Tokyo,
Japan) (1, 3, and 10 mg/kg, n = 4 in each), CP-100,263 (Pfizer, Tokyo, Japan) [10 mg/kg, n = 4; the
enantiomer of CP-99,994 with a very low affinity for NK1
receptor (33)], or a low dose of NMDA receptor antagonist
MK-801 (Sigma, St. Louis, MO) (1 mg/kg, n = 4) on
spinal c-fos expression were investigated. To examine nonspecific antinociceptive effects of CP-99,994 in rats, a high dose
(10 mg/kg) of CP-100,263 was used. All drugs were dissolved in saline.
For control animals without drug administration, the same amount of
saline was administered intravenously as a vehicle. Effect of
coadministration of a low dose of CP-99,994 (1 mg/kg) and MK-801 (1 mg/kg) was also examined (n = 4). CP-99,994 and MK-801
were administered 15 min before the start of lower urinary tract irritation.
Two hours after infusion of acetic acid, the animals were killed via
intracardiac perfusion of 0.1 M phosphate buffer (PB), pH 7.4, followed
by 4% paraformaldehyde fixative in PB (0.1 M, pH 7.4). The spinal cord
was then removed and postfixed for 24 h in the same fixative at
4°C before cryoprotection in 0.1 M (pH 7.4) phosphate-buffered 30%
sucrose solution overnight. With the use of avidin-biotin complex (ABC)
method, alternate sections (30 µm) of the spinal cord were processed
for immunoreactivity to c-fos protein (Fos), using nickel
intensification (1-3, 16). Sections were incubated in
Fos antiserum diluted for 2% rabbit serum in Tris-buffered saline
(0.05 M, pH 7.6) containing 0.5% Triton X-100 (1:500; Chemicon) for
80 h at 4°C, and then in biotinylated secondary antibody
(1:1,000, Chemicon) and ABC reagent (Chemicon), each for 2 h at
room temperature. Tissue sections were then mounted on gelatin-coated
slides, dehydrated in graded ethanol, cleared in xylene, and placed
under a coverslip with Permount. All sections were examined with
bright-field microscopy.
Because previous studies analyzed the distribution of Fos-positive
cells within the spinal cord (2, 10), analysis in the
present study was restricted to the L1 and L6
spinal segment, where the majority of the hypogastric and pelvic nerve
afferent terminals project, respectively. Cells exhibiting Fos
immunoreactivity were counted in three different spinal cord regions:
dorsal horn (DH), dorsal commissure (DCM), and intermediolateral gray
matter (ILG) (Fig. 1, A and
B). In the L1 spinal segment, because the number
of Fos-positive cells in the DCM and ILG regions was significantly smaller than in the DH, the number of Fos-positive cells in the DCM and
ILG was counted together (Fig. 1A). Counts of
Fos-positive cells were performed on 20 sections. All values in the
text are expressed as means ± SE. To evaluate changes in the
number of Fos-positive cells in each group, analysis of variance
followed by the Mann-Whitney U-test was used for examining
differences in the distribution of Fos-positive cells at specific areas
of the spinal cord, and P < 0.05 was considered
significant.
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Fig. 1.
Drawing of section from the L1 and
L6 spinal cord of the rat showing 3 regions where
Fos-positive cells were identified. A: L1 spinal
cord. 1, dorsal horn (DH); 2, dorsal commissure (DCM) and
intermediolateral gray matter (ILG). B: L6
spinal cord. 1, DH; 2, DCM; 3, ILG.
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RESULTS |
Effects of NK1 receptor antagonist on c-fos expression.
The total number of Fos-positive cells after lower urinary tract
irritation was 53 ± 7 and 108 ± 6 cells/section at the
L1 and L6 spinal cord, respectively
[Figs. 2A
(L6) and 3A
(L1)]. The largest number of Fos-positive
cells at the L6 spinal cord was located at the DCM area
(44 ± 3 cells/section), with smaller numbers at the ILG (34 ± 3 cells/section) and DH (30 ± 3 cells/section). At the
L1 spinal cord, the number of Fos-positive cells was much greater at the DH (44 ± 4 cells/section) than at DCM and ILG
(8 ± 2 cells/section).
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Fig. 2.
Photographs of the L6 spinal cord of rats
treated with intravesical acetic acid infusion. Fos-positive cells were
identified by dark spots within the nuclei. A: control. The
largest number of Fos-positive cells at the L6 spinal cord
was located at the DCM area, with smaller numbers at the ILG and DH.
B: administration of high dose (10 mg/kg) of CP-99,994
reduced the number of Fos-positive cells at all 3 regions.
C: coadministration of a low dose (1 mg/kg) of CP-99,994 and
MK-801 reduced the number of Fos-positive cells at all 3 regions.
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CP-99,994 dose dependently reduced the total number of Fos-positive
cells at both levels of the spinal cord (Table
1, Figs. 2B and
3B). However, CP-100,263 (10 mg/kg iv), the enantiomer of
CP-99,994, did not affect the total number and regional difference of
Fos-positive cells compared with control (Table 1).
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Table 1.
Effects of drugs on the number of Fos-positive cells after lower
urinary tract irritation with acetic acid infusion
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Fig. 3.
Photographs of the L1 spinal cord of rats
treated with intravesical acetic acid infusion. Fos-positive cells were
identified by dark spots within the nuclei. A: control. The
number of Fos-positive cells was much greater at the DH than at DCM and
ILG. B: administration of high dose (10 mg/kg) of CP-99,994
reduced the number of Fos-positive cells at the DH region.
C: coadministration of a low dose (1 mg/kg) of CP-99,994 and
MK-801 reduced the number of Fos-positive cells at the DH region.
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At the L1 spinal cord, the number of Fos-positive cells
after 1, 3, and 10 mg/kg of CP-99,994 was 96 ± 3, 90 ± 3 (P < 0.05), and 56 ± 2% (P < 0.01) of control, respectively, while at the L6 spinal cord
the number of Fos-positive cells after 1, 3, and 10 mg/kg of CP-99,994
was 96 ± 4, 83 ± 4 (P < 0.03), and 35 ± 6% (P < 0.01) of control, respectively (Table 1,
Fig. 4). Regional differences were
observed in the effects of CP-99,994. At the L1 spinal
cord, CP-99,994 did not have a significant effect on the number of
Fos-positive cells at the DCM + ILG regions, whereas CP-99,994
decreased the number of Fos-positive cells in a dose-dependent manner
at the DH region of the L1 spinal cord (Table 1, Fig. 5A). At the DH region of the
L1 spinal cord, the number of Fos-positive cells after 1, 3, and 10 mg/kg of CP-99,994 was 97 ± 3, 90 ± 4 (P < 0.03), and 50 ± 2% (P < 0.01) of the control, respectively (Table 1). At the L6
spinal cord, CP-99,994 reduced the number of Fos-positive cells in a
dose-dependent manner at all three regions. The number of Fos-positive
cells after 1, 3, and 10 mg/kg of CP-99,994 was 96 ± 4, 78 ± 3 (P < 0.03), and 27 ± 7% (P < 0.01) of the control at the DCM; 99 ± 6, 91 ± 5 (P < 0.05), and 37 ± 4% (P < 0.01) of the control at the ILG; and 96 ± 4, 80 ± 7 (P < 0.03), and 44 ± 7% (P < 0.01) of the control at the DH of the L6 spinal cord,
respectively (Table 1, Fig. 5B).
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Fig. 4.
Effects of graded doses of CP-99,994 (CP) on the total
number of Fos-positive cells at the L1 and L6
spinal cord after low urinary tract irritation (n = 4 in each dose). Percent changes in the number of Fos-positive cells per
section are indicated. * P < 0.05, ** P < 0.03, *** P < 0.01 compared with control (vehicle).
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Fig. 5.
Regional differences in the effect of graded doses of
CP-99,994 on the number of Fos-positive cells at the L1 and
L6 spinal cord after low urinary tract irritation
(n = 4 in each dose). Percent changes in the number of
Fos-positive cells per section are indicated. A:
L1 spinal cord. B: L6 spinal cord.
* P < 0.05, ** P < 0.03, *** P < 0.01 compared with control (vehicle).
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Effects of coadministration of NK1 receptor antagonist
and NMDA receptor antagonist on spinal c-fos expression.
Intravenous administration of a low dose of either CP-99,994 (1 mg/kg)
or MK-801 (1 mg/kg) alone did not significantly alter the number of
Fos-positive cells (Table 1, Figs. 6 and
7, A and B). At
the L1 spinal cord, the number of Fos-positive cells as percentage of the control after 1 mg/kg of MK-801 was 96 ± 3% in
total, 92 ± 1% at the DCM + ILG, and 95 ± 4% at the
DH, while at the L6 spinal cord it was 94 ± 2% in
total, 96 ± 4% at the DCM, 94 ± 5% at the ILG, and
91 ± 5% at the DH (Table 1). However, coadministration of a low
dose of CP-99,994 (1 mg/kg) and MK-801 (1 mg/kg) significantly reduced
the total number of Fos-positive cells at both levels of the spinal
cord: L1, 65 ± 2% (P < 0.01) of
control; L6, 47 ± 5% (P < 0.01) of
control (Table 1, Figs. 2C, 3C, and 6). Regional
differences were again observed in the effects of coadministration of a
low dose of CP-99,994 and MK-801. After coadministration of a low dose
of CP-99,994 and MK-801, the number of Fos-positive cells at the
L1 spinal cord decreased significantly only at the DH
region (59 ± 3% of the control) (Table 1, Fig. 7A),
whereas at the L6 spinal cord the number of Fos-positive cells decreased significantly at all three regions (40 ± 6, 47 ± 6, and 57 ± 3% of the control at the DCM, ILG, and
DH, respectively) (Table 1, Fig. 7B).
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Fig. 6.
Effects of coadministration of a low dose (1 mg/kg) of
CP-99,994 and MK-801 on the total number of Fos-positive cells at the
L1 and L6 spinal cord after low urinary tract
irritation (n = 4 in each dose). Percent changes in the
number of Fos-positive cells per section are indicated for pretreatment
with a low dose of either CP-99,994 or MK-801 alone, or a combination
of both (CP + MK) before lower urinary irritation.
* P < 0.01 compared with control (vehicle).
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Fig. 7.
Regional differences in the effect of coadministration of
a low dose (1 mg/kg) of CP-99,994 and MK-801 on the number of
Fos-positive cells at the L1 and L6 spinal cord
after low urinary tract irritation (n = 4 in each
dose). Percent changes in the number of Fos-positive cells per section
are indicated for pretreatment with a low dose of either CP-99,994 or
MK-801 alone, or a combination of both before lower urinary irritation.
A: L1 spinal cord. B: L6
spinal cord. * P < 0.01 compared with control
(vehicle).
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DISCUSSION |
In the present study, c-fos expression in spinal
neurons was used to examine the role of NK1 receptor and
the possible interaction between NK1 and NMDA receptors in
spinal nociceptive pathways activated by afferent input from the lower
urinary tract. Because CP-99,994, which was used as a selective
NK1 receptor antagonist in the present study, is known to
have nonspecific antinociceptive effects in rats (33), we
also examined its less active enantiomer, CP-10,263. CP-100,263 has the
same nonspecific antinociceptive effects but has a very low affinity
for NK1 receptor (33). CP-100,263 showed no
significant effect on c-fos expression after lower urinary tract irritation. Therefore, the results indicate that NK1
receptor is involved in spinal c-fos expression after lower
urinary tract irritation. A previous study on c-fos
expression has shown that glutamatergic receptors (NMDA and non-NMDA
receptors) play a synergistic role in bladder nociceptive processing
(16). The results in the present study further indicate
that NK1 and NMDA receptors have a synergistic interaction
in the spinal processing of bladder nociception.
Role of NK1 receptor in spinal c-fos expression after
lower urinary tract irritation.
Systemic administration of CP-99,994, which has central actions after
intravenous administration (33), reduced dose dependently the total number of Fos-positive cells at the L1 and
L6 spinal cord after lower urinary tract irritation.
However, the effects of CP-99,994 on c-fos expression at
specific regions within the spinal cord were different between the
L1 and L6 spinal cord. At the L6
spinal cord, the reduction of Fos-positive cells by CP-99,994 was noted
at all three regions within the spinal cord. In contrast, the reduction
of Fos-positive cells at the L1 spinal cord was restricted
to the DH region. Thus it seems that spinal neurons located at the DCM
and ILG of the L1 spinal cord that are involved in
c-fos expression are insensitive to NK1 receptor antagonist. The number of Fos-positive cells at the L1
spinal cord was significantly smaller at the DCM and ILG regions
(8 ± 2 cells/section) than at the DH (44 ± 4 cells/section). This finding is consistent with a previous study that
revealed that an increase in c-fos expression at the
Th12-L2 spinal cord after lower urinary tract
irritation was mainly noted in lamina I (10). Thus, at the
L1 spinal cord, where the hypogastric nerve afferent
terminals project, the effects of CP-99,994 was only noted at the DH
region, which contains numerous nociception-specific neurons.
In accordance with the present study, Fos-positive neurons after
chemical stimulation of the bladder with formalin were distributed in
the DCM, ILG, and DH of the L6-S1 spinal
cord where the spinal micturition center of the rat exists
(20). These Fos-positive neurons in the
L6-S1 spinal cord appear to be distributed
in the areas of distribution of nociceptive spinal neurons that have been identified electrophysiologically (26).
Interestingly, the distribution of these Fos-positive neurons was quite
similar to that of substance P receptor-like immunoreactive neurons,
and more than 80% of substance P receptor-like immunoreactive neurons in the DCM, ILG, and DH exhibited Fos immunoreactivity after
nociceptive bladder stimulation (20). Taken together, it
may be speculated that activation of NK1 receptors in the
spinal neurons by nociceptive bladder stimulation is involved in
inducing c-fos expression. Thus NK1 receptor
antagonism by CP-99,994 significantly reduced c-fos
expression in the preset study, suggesting that NK1
receptor is involved in spinal processing of nociceptive input from the lower urinary tract. These results are consistent with previous findings that NK1 receptor antagonists inhibited
nociceptive reflex responses to chemical stimulation of the gallbladder
and to jejunal distension (28, 33). An essential role of
NK1 receptor mediating central responses to nociceptive
visceral stimulation (chemical stimulation of colon and
cyclophosphamide-induced cystitis) has been well demonstrated in mice
with a disruption of the NK1 receptor gene
(17). However, because a large dose of NK1
receptor antagonist used in the present study did not block completely
c-fos expression in spinal neurons, substance P may have a
neuromodulatory, as opposed to absolute neurotransmitter, role in
spinal processing of nociception (6).
Interaction between NK1 and NMDA receptors in spinal
c-fos expression after lower urinary tract irritation.
It has been shown that NMDA glutamatergic receptor in spinal neurons is
involved in visceral nociception. Preemptive intrathecal administration
of NMDA receptor antagonist prevents hyperreflexia in a model of
persistent visceral pain (32). Visceral hyperalgesia induced by colonic inflammation is mediated by the activation of spinal
NMDA receptor (9). Thus many studies implicate the critical role of NMDA receptor in visceral pain (5). The
present study, as the second part of experiments, focused on the
possible interaction between NK1 and NMDA receptors in
spinal processing of visceral nociception, instead of the
well-documented role of NMDA receptor in visceral nociception.
Previous studies have shown that intravenous administration of a high
dose (3.5 mg/kg) of MK-801 but not a low dose (0.8-1 mg/kg)
significantly reduced spinal c-fos expression after chemical irritation of the lower urinary tract (1, 3, 16). The mean
reduction of Fos-positive cells in the L6 spinal cord after intravenous administration of 3.5 mg/kg of MK-801 was 53, 55, and 54%
at the DCM, ILG, and DH (1). In the present study, intravenous administration of a low dose (1 mg/kg) of either CP-99,994 or MK-801 alone did not significantly alter the number of Fos-positive cells. We selected only a dose of 1 mg/kg of MK-801 to confirm the
ineffectiveness of a low dose of MK-801 in suppressing spinal c-fos expression after lower urinary tract irritation.
However, combined administration of a low dose of CP-99,994 and MK-801 significantly decreased the number of Fos-positive cells at the L1 (35% reduction) and L6 spinal cord (53%
reduction) to the almost similar extent as that observed after
administration of the highest dose (10 mg/kg) of CP-99,994. In the
L6 spinal cord, the mean reduction of Fos-positive cells
after coadministration of a low dose of CP-99,994 and MK-801 was 60, 53, and 43% at the DCM, ILG, and DH, respectively. Compared with the
results of a previous study (1), this inhibitory effect of
coadministration of a low dose of CP-99,994 and MK-801 on spinal
c-fos expression was equivalent to that of a high dose of
MK-801. From these results, it seems that the effect of
coadministration of a low dose of CP-99,994 and MK-801 is not simply
additive, but there must be synergism between the NK1 and
NMDA receptor antagonists. Because the present study did not focus on
the dose-response characteristics of MK-801, we did not examine the
effect of a medial (e.g., 2 mg/kg) or high dose of MK-801. Despite such
limitations in the present study, we believe that NK1 and
NMDA receptors have a synergistic interaction in the spinal processing
of nociceptive input from the lower urinary tract.
A variety of studies has demonstrated mechanisms underlying the
interaction between NK1 and NMDA receptor-mediated events. Synergistic activation of NK1 and NMDA receptors is
anatomically possible because both receptors have been reported to
coexist on single dorsal horn neurons (31, 35). The
release of substance P is controlled by facilitatory NMDA receptors
(11, 18, 21) and then the released substance P can also
enhance the basal release of EAAs (34). Systemic
coadministration of NK1 receptor antagonist and NMDA
receptor antagonist significantly reduced the number of Fos-positive
cells after intraplantar formalin injection, and the attenuating effect
of the coadministration was significantly greater than the effect of
either the NK1 or NMDA receptor antagonist alone
(6). These results are consistent with the present study. Thus cooperativity between NK1 and NMDA receptors within
the spinal cord, which has been shown in somatic nociceptive pathways
as stated above, was also demonstrated in visceral nociceptive pathways by the present study.
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ACKNOWLEDGEMENTS |
We are grateful to Pfizer Pharmaceutical for a gift of CP-99,994
and CP-100,263.
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FOOTNOTES |
Address for reprint requests and other correspondence: T. Mitsui, Dept. of Urology, Hokkaido Univ. Graduate School of Medicine, North-15, West-7, Kita-Ku, Sapporo, 060-8638, Japan (E-mail:
mitsui68{at}med.hokudai.ac.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00582.2001
Received 21 September 2001; accepted in final form 6 May 2002.
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INTRODUCTION
