Involvement of the 5-HT3 receptor in
CRH-induced defecation in rats
Keiji
Miyata1,
Hiroyuki
Ito1, and
Shin
Fukudo2
1 Pharmacology Laboratories,
Institute for Drug Discovery Research, Yamanouchi
Pharmaceutical, Tsukuba, Ibaraki 305; and
2 Department of Psychosomatic Medicine, Tohoku
University School of Medicine, Aoba-ku, Sendai 980, Japan
 |
ABSTRACT |
We evaluated the possibility
that serotonin (5-HT) mediates defecation induced by
corticotropin-releasing hormone (CRH) exogenously administered or
released from the central nervous system by stress via the
5-HT3 receptor in rats. Intracerebroventricular (ICV) injection of CRH (1, 3, and 10 µg/rat) dose dependently increased the
number of stools excreted in rats, whereas intravenous (IV) injection
of up to 100 µg/kg CRH did not affect defecation.
-Helical CRH-(9
41) and 5-HT3 receptor antagonists ramosetron and
azasetron inhibited CRH (10 µg icv)-induced defecation in a
dose-dependent manner with ED50 values of 4.3 µg/kg iv,
3.8 µg/kg po, and 70.4 µg/kg po, respectively.
-Helical
CRH-(9
41) also inhibited CRH-induced defecation by ICV injection with
an ED50 value of 0.078 µg/rat. In contrast, ramosetron
and azasetron injectied ICV had no effect on CRH-induced defecation.
-Helical CRH-(9
41), ramosetron, and azasetron reduced defecation
caused by restraint stress with ED50 values of 0.32, 3.6, and 19.7 µg/kg iv, respectively. These results indicate that CRH
exogenously administered or released from the central nervous system by
stress peripherally promotes the release of 5-HT, which in turn
stimulates defecation through the 5-HT3 receptor.
serotonin3 receptor; corticotropin-releasing hormone; ramosetron; azasetron
 |
INTRODUCTION |
MANY STUDIES HAVE REVEALED an association between the
occurrence of stressful experiences and the appearance of disturbances in bowel function in animals and humans, indicating that gut functions such as gastric emptying, gastric secretion, gastrointestinal transit,
and fecal pellet output are affected by various stresses (20, 23, 29).
Endogenous corticotropin-releasing hormone (CRH) is suggested to
mediate stress-induced changes in gut function (3, 10, 19, 22, 24, 26,
30). The action of CRH is centrally mediated through CRH receptors, and
CRH-induced alteration of gut function appears to be primarily mediated
by vagal efferent pathways (4, 10, 13, 25).
In recent years the role of serotonin (5-HT) as a neurotransmitter has
been recognized, and it is widely believed that 5-HT is extensively
involved in psychic and neural function. Miyata et al. (16) have
suggested that endogenous 5-HT is one of the substances to mediate
stress-induced responses of gastrointestinal function, such as
defecation and diarrhea, and that the effects of 5-HT are mediated by
the peripheral 5-HT3 receptor. Therefore, it is suggested
that CRH centrally released by stress mediates changes in colonic
function through the peripheral release of 5-HT.
In the present study we examined the effects of 5-HT3
receptor antagonists ramosetron and azasetron and the CRH receptor
antagonist
-helical CRH-(9
41) on defecation induced by restraint
stress and intracerebroventricular (ICV) administration of CRH in rats and investigated the possibility that 5-HT acts as a mediator of
stress- and CRH-induced defecation.
 |
MATERIALS AND METHODS |
Animals.
Male Wistar rats weighing 200-370 g were used. The animals were
maintained on ordinary laboratory chow and tap water ad libitum under a
constant 12:12-h light-dark cycle.
Intracerebroventricular cannulation.
The rats were anesthetized with pentobarbital sodium (50 mg/kg ip) and
placed in a stereotaxic apparatus (Korf Instruments). The musculature
on the skull was removed, and the skull was exposed. After a hole was
drilled through the skull with a hand-operated drill (Lancelot; Tokyo
Nakai, Japan), a cannula for ICV injection of drugs was inserted
perpendicularly into the right lateral ventricle (coordinates: 0.8 mm
caudal to bregma, 1.5 mm lateral from midline, 3.4 mm ventral from
dura) and fixed to the skull with resin (Ortho Crystal; Rocky Mountain
Morita). Experiments were performed at least a month after surgery.
Rats with cannulas for ICV injection were used several times at an
interval of a week or more. All drugs were administered in a volume of
10 µl over a period of 1-min under light anesthesia with ether.
Effect of CRH on defecation in rats.
Initial experiments were conducted in the fed rat to determine the
effects of ICV CRH administration on defecation. Preliminary experiments showed that CRH increased fecal pellet output. To determine
doses for the following studies, the dose-response curve for
CRH-induced fecal pellet output was therefore determined using approximately threefold increases in the CRH dose. Because the effect
of CRH on defecation lasted for ~2 h, the number of fecal pellets
expelled by each animal was measured 2 h after CRH injection. Inhibitory activity of the test drugs was evaluated in CRH (10 µg/rat
icv)-induced fecal pellet output.
-Helical CRH-(9
41), which is a
peptide and is seldom absorbed from the gastrointestinal tract, was
administered intravenously (IV) 5 min before CRH administration under
restraint condition, whereas ramosetron and azasetron were given orally
to rats 1 h before CRH to avoid stress based on drug administration. In
the case of ICV administration, test drugs were given just before CRH
administration under light anesthesia with ether. In another experiment
the effect of IV CRH on defecation was examined to confirm the
effective site of CRH, either central or peripheral.
Effect of restraint stress on defecation in rats.
The stress model used in the present study was restraint stress (17).
Animals were stressed by placing them in individual compartments of
special stress cages (Natsume Seisakusho; Tokyo, Japan; 265 mm
wide × 95 mm long × 200 mm high) at room temperature (23°C).
The effect of the test drugs on stress-induced increases in pellet
output was determined 1 h after the beginning of the restraint stress.
Test drugs were injected IV just after exposure to restraint stress.
Statistical evaluation.
All values are means ± SE or the mean with 95% confidence limits
(CL). The statistical significance of values for fecal
pellet output was determined by Dunnett's multiple-range test.
Probabilities of <5% (P < 0.05) were considered
significant. ED50 values with 95% CL were calculated as
the dose causing 50% inhibition of the increase in stools excreted
(control) by log-probit analysis from data obtained for three or four
doses of each compound. All calculations were determined with reference
to concomitantly tested control animals.
Drugs.
Ramosetron hydrochloride (YM-060) and azasetron
hydrochloride (Y-25130) were prepared by Yamanouchi Pharmaceutical
(Tsukuba, Ibaraki, Japan). CRH and
-helical CRH-(9
41) were
purchased from Peptide Institute (Osaka, Japan) and Sigma Chemical (St.
Louis, MO), respectively. All drug doses were given as the free base. Ramosetron and azasetron were dissolved in physiological saline and
injected in rats in volumes of 2 ml/kg. CRH and
-helical CRH-(9
41)
were dissolved in distilled water and distilled water containing 3%
DMSO, respectively. In the case of oral administration, ramosetron and
azasetron were suspended in 0.5% methylcellulose solution and given to
rats in volumes of 5 ml/kg.
 |
RESULTS |
Effect of CRH on defecation in rats.
ICV injection of CRH (1, 3, and 10 µg/rat) dose dependently increased
the number of stools excreted (Fig.
1A), whereas IV CRH
injection did not affect defecation up to 100 µg/kg (Fig. 1B). Because macroscopic findings of fecal pellets and the
weight of each pellet were not affected by CRH at the highest dose of 10 µg/rat (data not shown), only the number of stools excreted by
each animal was measured in the following experiments.
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Table 1.
Effects of -helical CRH-(9 41), ramosetron, and
azasetron on CRH- and restraint stress-induced increases in number of
stools excreted by Wistar rats
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Fig. 1.
Effect of intracerebroventricular (ICV; A) and intravenous
(IV; B) injection of corticotropin-releasing hormone (CRH) on
defecation in Wistar rats. CRH given ICV but not IV dose dependently
increased number of stools excreted. Each bar represents means ± SE
for 7-10 animals. * P < 0.05 and ** P < 0.01 compared with the control group (Dunnett's multiple-range
test).
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Blockade of CRH-induced increases in the number of stools excreted.
In control animals, ICV administration of CRH at 10 µg/rat resulted
in an increase in defecation, with a 2-h pellet output count of ~6.
As shown in Fig. 2A,
-helical
CRH-(9
41) significantly inhibited CRH-induced increases in fecal
pellet output at IV doses of 10 and 100 µg/kg, with an
ED50 (95% CL) of 4.3 (3.4-5.6) µg/kg iv (Table 1).
Ramosetron (10 and 100 µg/kg po) and azasetron (100 and 1,000 µg/kg
po) also significantly inhibited CRH-induced defecation with
ED50 values of 3.8 (0.7-19.4) and 70.4 (54.1-91.6) µg/kgpo, respectively (Fig. 2, B and
C; Table 1).
-Helical CRH-(9
41) (0.1 and 1 µg/rat) given
ICV just before CRH ICV injection also showed significant preventive
effects on CRH-induced increases in the number of stools excreted in
rats, with an ED50 value of 0.078 (0.01-0.52) µg/rat
icv (Table 1). On the other hand, neither ICV ramosetron (10 µg/rat)
nor azasetron (100 µg/rat) affected CRH-induced defecation (Fig.
3).

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Fig. 2.
Effects of IV -helical CRH-(9 41) (A), oral ramosetron
(B), and oral azasetron (C) on ICV CRH-induced
increases in the number of stools excreted by Wistar rats. -Helical
CRH-(9 41), ramosetron, and azasetron significantly inhibited
CRH-induced defecation, with ED50 values of 4.3 µg/kg iv,
3.8 µg/kg po, and 70.4 µg/kg po, respectively. Each bar represents
means ± SE for 7-10 animals. -Helical CRH-(9 41) was given
IV just before CRH (10 µg/rat) ICV injection, and ramosetron and
azasetron were given orally 1 h before CRH. * P < 0.05, ** P < 0.01, and *** P < 0.001 compared with
the control group (Dunnett's multiple-range test).
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Fig. 3.
Effects of ICV injection of -helical CRH-(9 41),
ramosetron, and azasetron on ICV CRH-induced increases in the number of
stools excreted by Wistar rats. -Helical CRH-(9 41) given ICV
significantly and dose dependently inhibited CRH-induced defecation
with an ED50 value of 0.078 µg/rat, whereas ramosetron
and azasetron had no effect. Each bar represents means ± SE for 8 animals. Test compounds were given ICV just before CRH (10 µg/rat)
ICV injection. *** P < 0.001 compared with the control
group (Dunnett's multiple-range test).
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Blockade of stress-induced increases in the number of stools
excreted in rats.
The changes in fecal pellet output in control rats during the
observation time were negligible. Restraint stress resulted in
increases in stools, with pellet output counts of 4.3 ± 1.1, 4.3 ± 0.6, and 5.7 ± 0.7 for the
-helical CRH-(9
41)-, ramosetron-, and
azasetron-control groups, respectively (n = 10). As shown in
Fig. 4,
-helical CRH-(9
41),
ramosetron, and azasetron significantly inhibited restraint
stress-induced increases in fecal pellet output, with ED50
values of 0.32 (0.22-0.46), 3.6 (3.2-4.1), and 19.7 (10.2-38.1) µg/kg iv, respectively (Table 1).

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Fig. 4.
Effects of IV -helical CRH-(9 41) (A), ramosetron
(B), and azasetron (C) on restraint stress-induced
increases in the number of stools excreted by Wistar rats. -Helical
CRH-(9 41), ramosetron, and azasetron significantly inhibited
restraint stress-induced defecation, with ED50 values of
0.32, 3.6, and 19.7 µg/kg iv, respectively. Each bar represents means ± SE for 10 animals. Test compounds were given IV just after
restraint stress. * P < 0.05, ** P < 0.01, and *** P < 0.001 compared with the control group
(Dunnett's multiple-range test).
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|
 |
DISCUSSION |
Endogenous CRH is thought to mediate stress-induced changes in colonic
function, such as colonic motility, transit, and fecal excretion (3,
10, 19, 22, 24, 26, 30), and the action of CRH is suggested to be
centrally mediated through CRH receptors and vagal efferent pathways
(4, 10, 13, 25). In the present study, ICV CRH dose dependently
increased the number of stools excreted by Wistar rats, whereas IV
injection of CRH did not affect defecation, confirming that CRH-induced
changes in bowel function are evoked centrally. In contrast, according to our preliminary experiments using Sprague-Dawley rats, IV CRH as
well as ICV CRH increased fecal pellet output in a dose-dependent manner (data not shown). The discrepancy of the effect of CRH when
given IV between Wistar and Sprague-Dawley rats may be due to the
difference in strain, especially in moving to the central nervous
system through the blood-brain barrier, although the exact reasons and
mechanisms are presently not understood.
A large portion of 5-HT in the body is found in gastrointestinal
tissue, where it plays an important physiological role in producing
smooth muscle contraction. Recently, 5-HT3 receptor cDNA of
human and rat was cloned (14). 5-HT3 receptors have been
found in the gastrointestinal tract by Northern blot and RT-PCR
analysis. Ramosetron and azasetron used in our study are 5-HT3 receptor antagonists (15, 21). These compounds
inhibited CRH-induced defecation in rats by IV injection, as well as
-helical CRH-(9
41), a CRH receptor antagonist. According to the
report by Miyata et al. (16), 5-HT released from enterochromaffin cells or enteric serotonergic neurons increases fecal pellet output excreted
in rats through the peripheral 5-HT3 receptor. Ramosetron suppressed CRH-induced fecal pellet output in doses to inhibit 5-HT-induced defecation. The inhibitory activity ratio of ramosetron and azasetron in CRH-induced defecation is approximately consistent with that in Bezold-Jarisch reflex mediated by 5-HT3
receptors in anesthetized rats (17). The activation of
5-HT4 receptors facilitates acetylcholine release from
enteric nerve terminals and leads to the enhancement of
gastrointestinal propulsion (27). Some of the gastrointestinal
prokinetic benzamides possess affinities for 5-HT4 as well
as 5-HT3 receptors (2, 7, 8). At least ramosetron, however,
shows neither 5-HT4 agonistic nor antagonistic properties
(18). All considered, the inhibitory effects of ramosetron and
azasetron on CRH-induced defecation are suggested to be based on their
5-HT3 receptor antagonistic properties. Furthermore, the
site of action of ramosetron and azasetron appears to be peripheral, since ICV injection of ramosetron and azasetron did not affect defecation caused by CRH. Central 5-HT is known to be a potent stimulant of hypothalamic CRH secretion (5). In contrast, there is no
report on the direct link between central CRH release and the
peripheral 5-HT release. Diop et al. (6) have suggested that the
release of central CRH by cold stress promotes the release of
thyrotropin-releasing hormone (TRH), which in turn directly controls
gastrointestinal function. TRH activates colonic transit via a vagally
mediated serotonergic mechanism (11). Weiner (28) has reported that TRH
increases 5-HT secretion into the stomach. Taken together, these
findings suggest that CRH centrally released by stress mediates changes
in colonic function through the peripheral 5-HT released from
enterochromaffin cells or enteric serotonergic neurons.
Endogenous 5-HT is suggested to be one of the substances to mediate
stress-induced responses of gastrointestinal function, such as
defecation and diarrhea (16). In the present study, ramosetron
inhibited CRH-induced defecation in doses to suppress restraint
stress-induced defecation in rats. Furthermore, a CRH receptor
antagonist
-helical CRH-(9
41) also inhibited fecal pellet output
excreted by restraint stress. On the other hand, endogenous CRH is
suggested to mediate stress-induced gastrointestinal dysfunction,
including defecation, as mentioned previously. Altogether, these
observations indicate that CRH exogenously administered or released
from the central nervous system by stress peripherally promotes the
release of 5-HT, perhaps from enterochromaffin cells located in
gastrointestinal mucosa, which in turn stimulates fecal pellet output
through the 5-HT3 receptor. Kawahito et al. (12) have
reported that colonic mucosal enterochromaffin cells in normal humans
produce CRH and have indicated that CRH in the colonic mucosa may play
a role in modulation of the gastrointestinal functions basally during
stressful conditions as well as the intestinal immune system. In
addition to the central role of CRH therefore it is possible that
stress-induced defecation might be mediated at least in part at
peripherally located CRH receptors. This may be one possibility to
explain the difference in potency for
-helical CRH-(9
41) in the
CRH and stress models in the present study.
Gue et al. (9) have reported that peripheral 5-HT1 but not
5-HT2 and 5-HT3 receptors are involved in the
mediation of emotional stress-induced stimulation of colonic motility
and that 5-HT1A receptor agonists inhibit stress-induced
colonic dysfunction through the central activation of cholecystokinin
neurons. These results (9) and our own indicate that endogenous 5-HT
not only directly stimulates colonic motility through the
5-HT3 receptor but also indirectly inhibits colonic
hypermotility through the 5-HT1A receptor.
As described before,
-helical CRH-(9
41) given IV as well as ICV
inhibited CRH-induced defecation, whereas CRH given ICV but not IV
caused defecation in rats. Amtorp (1) has reported that substances with
a molecular weight of less than 5,500 are subjected to restricted
diffusion through the blood-brain barrier. The molecular weight of CRH
is ~5,000, indicating it to be borderline as to whether or not CRH
diffuses through the blood-brain barrier. On the other hand, the
molecular weight of
-helical CRH-(9
41) is four-fifths of that of
CRH. Therefore, at least a small amount of
-helical CRH-(9
41) is
expected to pass through the blood-brain barrier. In fact, the
inhibitory effect of peripheral
-helical CRH-(9
41) on CRH-induced
defecation (ED50, 4.3 µg/kg iv) was about 10 times less
potent than that of central
-helical CRH-(9
41) (ED50,
0.078 µg/rat icv, which corresponds to 0.2-0.4 µg/kg iv after
body weight correction) in the present study.
In conclusion, centrally administered CRH increased fecal pellet output
excreted by conscious Wistar rats. 5-HT3 receptor antagonists ramosetron and azasetron, similar to
-helical
CRH-(9
41), inhibited not only restraint stress- but also CRH-induced
defecation. Therefore, it is suggested that endogenous CRH centrally
released by stress peripherally promotes the release of 5-HT, which in turn increases defecation through the 5-HT3 receptor.
 |
FOOTNOTES |
Address for reprint requests: K. Miyata, Pharmacology Laboratories,
Inst. for Drug Discovery Research, Yamanouchi Pharmaceutical, 21 Miyikigaoka Tsukula, Ibaraki 305, Japan.
Received 9 January 1997; accepted in final form 13 February 1998.
 |
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