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The κ agonist fedotozine modulates colonic distention-induced inhibition of gastric motility and emptying in dogs
GASTROENTEROLOGY 1994;107:1327-1334
The ICAgonist Fedotozine Modulates Colonic DistentionInduced Inhibition of Gastric Motility and Emptying in Dogs MICHiLE
GUI?,*,’ JEAN LOUIS JUNIEN,* and LIONEL BUtNO+
*Institut de Recherche Jouveinal, Fresnes; and +Depattment of Pharmacology, lnstitut National de la Recherche Agronomique, Toulouse, France
Gastric motor disturbances, associated with a delay in gastric emptying, occur in patients with the irritable bowel syndrome. The influence of fedstozine and K agonists on the cologastric reflex produced by nonpainful colonic distention was evaluated in conscious dogs. Methods: Colonic distention was applied in dogs fitted with either strain gauges or gastric cannula to assess its influence on gastrointestinal motility and gastric emptying, respectively. Results: Colonic distention delayed the occurrence of gastric migrating motor complex by 141%, an effect blocked by intravenous fedotozine, U 50 488 (25 and 50 ug/ kg), and hexamethonium (0.5 mg/kg) but not by PAla’, #methyl, Phe4, Gly5-ol enkephalin (1, 5, and 10 ug/ kg), granisetron (50 and 100 pg/kg), or bretylium to sylate (5 mg/kg). Nor-binaltorphimine hydrochloride (1 mg/kg intravenously) eliminated the suppressive action of fedotozine. Colonic distention reduced the lhour gastric emptying of solids by 40.1%, an effect blocked by fedotozine and U 50 488 (50 and 100 ug/ kg); nor-binaltorphimine hydrochloride (1 mg/kg) antagonized the blocking effect of fedotozine. Conclusions: Fedotozine acts through K receptors to block the colonic distention-induced delay on gastric motility and emptying. The cologastric reflex involves nicotinic ganglionic receptors but not adrenergic pathway and 5hydroxytryptamine 3 receptors. Backg~~nd/Aims:
M
otility disorders in different parts of the gastroin-
testinal tract have been implicated in various functional bowel disorders, such as the irritable bowel syndrome (IBS). Gastric motor disturbances, associated with a delay in gastric emptying, have been described recently in IBS’ and may result from an inhibitory reflex originating in the colon. Numerous studies have shown that distention of the colon or the rectum induces a decrease in gastric motility in dogs,2*3 rats,4 cats,’ and humans.6 Other studies in human volunteers showed that painless rectal distention induced inhibition of postprandial gastric contractions’ and gastric emptying.’ Neurally mediated gastric motor inhibition may be caused by an inhibition of cholinergic excitation, adrenergic stimulation, or
nonadrenergic, noncholinergic (NANC) inhibition.” The cologastric
inhibitory
sympathetic
reflex was reported to have both
and vagal
components.
Abrahamson
et
al. “J* showed that NANC vagal efferents are involved in the inhibition of gastric motility in response to noxious stimuli and suggest that these efferents are excited by distention
of the colon.12 Duodenal distention
in dogs
induced a vagally mediated NANC gastric relaxation.13 Fedotozine is a new compound acting peripherally as an agonist on K-opioid receptors.14*‘5 Fedotozine restores the gastric migrating
motor complex (MMC) inhibited
by acoustic stress in dogs16 and suppresses the surgical ileus-induced
intestinal
motor
inhibition
in
rats
through peripheral K receptors.” The aims of this study were to develop a model of nonpainful prolonged distention
of the proximal colon
in awake dogs to determine the effect of distention on gastrointestinal motility in the fasted state and on gastric emptying of a standard nutrient meal and to determine the involvement of cholinergic and/or adrenergic pathways on the viscerovisceral reflex. Additionally, we aimed to evaluate the influence of fedotozine on the cologastric inhibitory reflex on motility and gastric emptying and to determine its mechanism of action by comparing its effect with those of U 50 488 (a K agonist) and D-Ala2, N-methyl-Phe4-, Gly5-01 ekephalin (DAMGO) (a p-receptor agonist). Because it has been reported recently that 5-hydroxytryptamine 3 (5-HT3) receptor antagonists reduce the gastric response to duodenal distention,18 granisetron was also tested.
Materials and Yethads Animal Preparation Gastrointestinal motility. Six adult beagle dogs weighing lo- 13 kg were used. Under halothane (Fluothane Abbnwiations used in this paper: DAMGO, BAla’, Nmethyl, Phe4, Gly%l enkephalln; IHTI, 5hydroxytryptamine 3; IGS, irritable bowel syndrome; NANC, nonadrenerglc, nonchollnerglc; MMC, mlgratlng motor complex; norBNI, nor-blnaltorphlmlne hydrochloride. 0 1994 by the American Gastroenterological Association 00165085/94/$3.OC
1328
ND, and
GASTROENTEROLOGY Vol. 107, No. 5
GUE ET AL.
Coopers,
Maux) anesthesia,
a cecostomy
Llmll
was performed
PIWSSU~
two strain-gauge
method
transducers were implanted using a described, l9 one on the stomach 7 cm from
previously
the pylorus and the other on the proximal the ligament
of Treitz.
subcutaneously allowed
of canned
60 cm from
wires were brought
to the back of the neck, and the animals
15 days to recover before beginning
Each day at 5 21.7%
jejunum
The strain-gauge
PM,
food (Fido-Quaker,
dry matter,
Bordeaux,
7.7%
protein,
drates, and 2.6% minerals.
Water
Gastric
emptying. Four
weighing
lo-12
a Thomas
cannula
fat, 6.9%
male
beagle
adult halothane
was placed on the greater
on the left abdominal mals were allowed
to recover for 2 weeks before tests.
Motility recordings. Gastrointestinal
gauge was calibrated clamped
firmly
in a horizontal
strain gauge, and weights from the soldering
point.
the first recording
session,
ages were applied to calibrate kadenki,
1 mm lateral
(in millivolts)
curve was calculated. direct
was Before
current
the potentiometric
volt-
recorder (Ri-
of 400 g of canned
France) containing
food (Rox, Quaker,
21.7% dry matter,
4.5% fat, 6.9% carbohydrates,
7.7% protein,
and 2.6% minerals
from sheep intravenously
10 PCi [57Co]cyanocobalamine act, 10 l.HXpg) consisted
and killed
beled with 0.5 PCi [‘*C]PEG
(NEN
with
measured.
phase
water marker, Products,
after determination of five samples
(4-5
scintillation
contents
Bos-
eating,
was performed
1
were homogenized
taken; each sample of
and 57Co was counted
(SL 40; Intertechnique,
France). The rate of gastric emptying calculated
from these measurements
120
was performed
for each animal,
the balloon
increments
to a maxi-
The threshold
was reached when the animals showed
(contractions
of the abdomen,
lying on the
accompanied
by an increase
of at least 15% in heart rate. The compliance
of the balloon
before the experiments
by inflating
1). The balloon had a negligible
inside the colon represented the resistance the occurrence plied
the balloon
resistance,
especially the experi-
the intracolonic
pressure
and not
of the balloon. motility
of a gastric
for 90 minutes. was applied
studies,
40-50
MMC, colonic
For gastric immediately
dard meal and maintained
using
a
Plaisir,
of liquids and solids was as previously
described.”
ments, injection
and volume. Two series
mL) were rapidly
system
110
into the colon via the cecos-
the threshold
For gastrointestinal
la-
gamma counter (MR 252; Kontron, Basel, Switzerland). The second series was prepared for [‘*C]PEG determination using a liquid
100
minutes
distention
emptying
studies,
after ingestion
after
was apcolonic
of a stan-
for 1 hour, after which the gastric
were collected. Gastrointestinal motility. In the first series of experi-
contents
of the total weight
the first series was weighed,
inserted
floor, and sniffing the cecostomy),
minutes.
hour after the meal. The collected
90
mum of 120 mL. The balloon pressure and the heart rate were
contents
of the gastric
80
Procedure
balloon
tomy. To evaluate
‘*C; the meal was given to the animals for spontaneous collection
70 (ml)
was filled with water (37°C) by lo-mL
distention
Total
60
Colonic distention. Colonic distention using a lo-cm
ton, MA; sp act, 1 pCi/mg). The liquid phase was mixed with the solid phase after sampling 0.S mL for determination of which did not exceed 2-3
50
ments; we therefore assumed that the balloon pressure recorded
50 mg of polyeth-
Research
40
at 60 mL, which was the volume used throughout
Paris, France; sp
24 hours later. The liquid a nonabsorbable
30
Experimental
(Figure
Labeled
(IV) injected
(Amersham,
of 100 mL of tap water containing
ylene glycol (PEG) 4000,
20
means + SD; n = 12. A, mean intraballoon pressure for a volume of 60 mL. Dotted vertical lines indicate the lowest volumes at which heart rate changes and discomfort were observed. Note that for a volume of 60 mL, the resistance of the balloon is negligible and that the intraballoon pressure is equivalent to the intracolonic pressure.
was assessed
mixed with
sheep liver (20 g) labeled with [“Co]cyanocobalamine. liver was obtained
10
signs of discomfort
Determination of gastric emptying. The solid phase Bordeaux,
I
(+) or inserted into the proximal colon of dogs (l3). Results are
was
Tokyo, Japan).
of the meal consisted
0
at the level of the
corresponding
,
’
Each strain
The transducer
The amplitude
I
bridge ampli-
recorder.
(1 - 5 g) were attached
noted, and an average calibration
ac-
by connecting
Wheatstone
position
-
Figure 1. Changes in pressure vs. volume of balloon on the bench
The ani-
mechanical
23 hours/day
before implantation.
30
of the
It was exteriorized
was also performed.
fier (Vishay, France) and a potentiometric
_
Volume
wall 5 cm from the last rib and 10 cm
the strain gauges to a four-channel
40
anesthesia,
A cecostomy
continuously
_
dogs
curvature
from the midline.
tivity was recorded
50
carbohy-
ad libitum.
gastric body about 10 cm from the pylorus.
-
containing
was available
kg were used. Under
60
of hami rate changs
meal of 500 g
France),
4.5%
-
were
the experiments.
the dogs received a standard
70
OmW)
colonic
distention
was preceded
(10 minutes)
of vehicle (saline) alone or with fedotozine
by IV (10, 25,
or 50 pg/kg), U 50 488 (10, 25, or 50 yg/kg), or DAMGO (1, 5, or 10 pg/kg). In a second series of experiments, norbinaltorphimine hydrochloride (nor-BNI; 1 mg/kg), a specific K-receptor antagonist, or naltrindole, a specific a-receptor antagonist (100 pg/kg), were injected IV 10 minutes before fedotozine (50 p/kg IV). Colonic distention was performed 10 minutes after the last IV injection as in the first series of experiments. In a third series of experiments, to evaluate a
November 1994
FEDOTOZINE AND COLOGASTRIC REFLEX
The protocols
Table 1. Influence of Fedotozine on Maximum and Minimum lntracolonic Pressures pressure (mm Hg)
lntracolonic
Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV)
mentation
were approved
Committee
Maximum pressure
Minimum pressure
34.2 k 3.8 34.8 2 4.3
10.2 + 4.3 10.7 k 3.8
Evaluation The
lowest
ally detectable increase
of Pain Threshold pressure
thresholds
were performed
in dogs receiving
an IV injection
90 and
100 mL, respectively
alone (control) or saline with fedotozine
(50 pg/kg);
was filled with warm water (37°C) by lo-mL maximum
of 120 mL. In a fourth
antagonist; nicotinic
50 and 100 pg/kg), blocking
sympathetic istered
hexamethonium
ganglionic
blocking
IV 10 minutes
Each treatment
to a
agent, 5 mg/kg)
(n = 12 experiments)
(a
were assessed by measuring of the MMC pattern. SD and were compared
Motor
of gastric
of variance
mechanical
disruption as means
+
and paired
t
gastric
activity
fedototine
of vehicle alone or vehicle
or U 50 488 (10, 50, and
before
feeding.
Immediately
test meal, the colon was distended experiments. which
The distention
the gastric
of experiments,
contents
nor-BNI
before fedotozine
were collected.
series. Each treatment
was performed
was performed
for a P value I
Compounds. The fedotozine,
in triplicate
using a Wilcoxon
0.05. Results
following
U 50 488, and nor-BNI
analysis
matched-pair significant
as mean -f: SD.
compounds were synthesized
were
injected or gastric
All drugs
at doses that had no effect on gastrointestinal emptying.
the whole distention
Colonic
for 20 hours,
occurring distention
MMC continued
3). Compliance
the control
at 113.4
+ 18.6-minute
(60 mL) delayed MMC
by 141%,
at a normal
curves indicated
antral
by cyclic phases of the occurwhereas
frequency
that for a volume
the
(Figure of 6O-
mL, colonic pressure was 33.0 ? 5.4 mm Hg (Figure 1). The time interval between the first and second gastric MMC after colonic distention
was not significantly
ent (P > 0.05) from the control
interval.
differ-
No difference
used:
2
d 2 t t
30
P
by Jouve-
France). in saline.
its never
test meal
tron was a gift by SK Beecham (Paris, France); and naltrindole was purchased from Sigma Chimie (St. Quentin Fallavier, were dissolved
and the balloon pressure
series
inal (Fresnes, France); hexamethonium, bretylium tosylate, and DAMGO were purchased from RBI (Illkirch, France); granise-
All compounds
of 60 mL. during
in each dog
were considered
are expressed
of the colon
90
as in the previous
of animals,* statistical
test, and differences
with a volume
the
during
10 minutes
order.
Because of the small number signed-rank
In a second
IV), and the radiolabeled
after the last injection
of the results
for 1 hour, after
(1 mg/kg IV) was injected
(50 pg/kg
10
of the
as in the first part of the
was given 10 minutes in a randomized
100 pg/kg)
after ingestion
was maintained
pressure
was characterized
contractions
intervals. jejunal
Gastric emptying. In the first series of experiments,
minutes
adap-
we recorded
Studies
rence of the next gastric
the dogs were given an IV injection
used was 35 % a putative
1).
In dogs fasted
effects
test.
with
distention
of
were admin-
are expressed
by analysis
balloon
by the balloon,
Motility
order.
the duration
The values
of colonic
time (Table
twice in each of the six dogs
in a randomized
of balloon
exceeded 34.2 + 3.8 mm Hg during
tosylate
before colonic distention.
was applied
minimum
k 7.2
1). Consequently,
To evaluate
was no accommodation
distention
(5-HT,
(ganglionic
or bretylium
There
(Figure
the volume
0.05)
to a volume
of the colon to distention, and
minutes
the balloon
increments
series, granisetron
agent, 0.5 mg/kg),
maximum
of saline
(P 5
in heart rate for the six dogs were 44.8
and 50.2 + 5.9 mm Hg, corresponding
tive reaction
curves
for visu-
recorded
and significant
40% below the threshold. on colonic tone, compliance
9 137 and 9208).
(agreements
discomfort
in all experiments,
effect of fedotozine
Experi-
Results
NOTE. Results are expressed as mean + SD (n = 12) during 90 minutes of colonic distention with a balloon filled with 60 mL of warm water (37°C).
possible
by the Midi-Pyre&es
1329
were
motility
0,x 0
. SlO
ib
l&l
VOLUME (ml) flgure 2. Influence of intravenous injection of fedotozine ( + ; 50 ug/ kg) and vehicle (m; 0.1 mL/kg) on intracolonic pressure response to increasing volumes of distention in fasted dogs. Results are expressed as mean k SD; n = 12. *P > 0.05.
GASTROENTEROLOGY Vol. 107, No. 5
GUE ET AL.
1330
Table 2. Effect of 5-HT3 Receptor Antagonist and Ganglionic Blockers on Colonic Distention-induced Gastric MMC Cycle
Table 3. Effects of Fedotozine, U 50 488, and DAMGO on Colonic Distention-Induced MMC in Fasted Dogs
Delay in
Gastric MMC cycle (min)
inhibition of Gastric
Gastric MMC cycle (min)
Drugs
Basal
Colonic distention
Drugs
Basal
Vehicle Hexamethonium 0.5 mg/kg IV Bretylium 5 mg/kg IV Granisetron 50 fig/kg IV 100 r.lg/kg IV
100.4 * 17.3
236.6 ? 26.6a
96.9 2 13.7
119.3 -c 30.8
130.8 ? 33.5
113.3 It 18.4
232.3 2 24.7”
103.4 rt 26.2 121.6 ? 44.3
241.7 + 34.3” 250.6 -c 27.8”
Saline (0.5 mL/kg IV) Fedotozine @g/kg IV) 10 25 50 U 50 488 (/&& /l’) 10 25 50 DAMGO @g/kg IV) 1 5 10
NOTE. Results are expressed as mean -t SE; n = 12. “Significantly (P 5 0.05) different from corresponding basal values.
in gastric viously
response
was observed
between
naive and pre-
tested dogs. Bretylium tosylate and hexamethonium.
methonium
(0.5 mg/kg
MMC duration
IV) did not modify
(Table 2) but prevented
tention-induced
inhibition
26.6 minutes tosylate
(5 mg/kg
Bretylium
IV) had no effect on gastric
cycle and did not affect (P > 0.05) the colonic tion-induced
lengthening
Fedotozine, U 50 488,
and DAMGO. When
did not affect the duration
cycle significantly
fedotozine
in-
229.4 5 29.5" 124.9 2 15.3 103.9 lr 9.9
105.3 2 15.7 97.0 ? 10.6 110.3 5 21.6
215.1 -c 28.4” 132.8 2 35.4 124.9 + 22.3
99.4 2 10.5 94.6 ? 23.2 92.5 * 12.2
201.9 + 25.1” 198.7 + 19.0” 211.6 -c 26.8”
mg/kg IV, nor-BNI had no effect on gastrointestinal motility and on colonic distention-induced gastric motor
inhibition
10 minutes
(Table
4). However,
administered
10
minutes before fedotozine (50 pg/kg IV), nor-BNI eliminated the inhibitory action of fedotozine on colonic distention-induced 4). In contrast,
inhibition naltrindole
the blocking
distention-induced Granisetron.
in fasted dogs,
of the gastric MMC
(P > 0.05). Injected
111.5 2 20.2 106.4 2 20.8 108.1 -c 20.9
NOTE. Results are expressed as mean ? SD; n = 12 assays. “Significantly (P 5 0.05) different from corresponding basal values.
to eliminate
(Table 2).
jected at IV doses of 25 and 50 pg/kg
colonic distention,
MMC disten-
of gastric MMC cycle (232.3 ?
24.7 vs. 236.6 ? 26.6 minutes)
fedotozine
(MMC
with 236.6 +
with control colonic distention).
+ 24.3”
the gastric
motility
compared
233.9
Hexa-
the colonic dis-
of gastric
cycle of 130.8 + 33.5 minutes
Colonic distention
pg/kg
of gastric
(100 pg/kg
MMC
IV) was unable
effect of fedotozine
gastric motor disturbance Granisetron
injected
IV had no effect on gastrointestinal
(Table
on colonic (Table 4).
at 50 and 100 motility;
in
before
(25 and 50 pg/kg IV) elim-
inated the colonic distention-induced
lengthening
of the
gastric MMC cycle (Table 3 and Figure 3). However, at a lower dose (10 pg/kg), fedotozine did not reduce the colonic distention-induced ble 3). Injected IV at 50 pg/kg,
gastric
motor
which prevented
changes
(Ta-
the effects
of colonic distention on the gastric MMC, fedotozine had no effect (P > 0.05) on the compliance curve compared with control (Figure 2). U 50 488 (25 and 50 pg/kg IV) also suppressed (P < 0.05) the inhibition of gastric MMC induced by colonic distention (Table 3 and Figure 3). At a lower dose, U 50 488 (10 Fg/kg IV) had no effect on colonic distentioninduced gastric motor inhibition (Table 3). In contrast, DAMGO (1, 5, and 10 pg/kg IV) had no effect on colonic distention-induced inhibition of gastric motility (Table 3). Nor-BNI and naltrindole. Injected at a dose of 1
Figure 3. Blockade of colonic distention-induced inhibition of gastric MMC by fedotozine and U 50 488 in fasted dogs. Note that colonic distention selectively delayed the occurrence of the gastric but not the jejunal MMC.
November 1994
FEDOTOZINE AND COLOGASTRIC REFLEX
Table 4. Effect of Nor-BNI and Naltrindole on Disinhibition by Fedotozine on Colonic Distention-induced Gastric Motor Inhibition
solids and liquids.
However,
ine (50 and 100 pg/kg tion-induced
reduction
on gastric emptying Colonic distention
Basal
kg, fedotozine induced
Control Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV) After nor-BNI Saline (0.5 mL/kg IV) Fedotozine (50 ug/kg IV) After naltrindole Saline (0.5 mL/kg IV) Fedotozine (50 f&!/kg IV)
96.9 ? 13.7 108.1 t 20.9
233.9 103.9
+ 24.3” 2 9.9
112.3 2 23.4 91.3 * 11.7
239.7 225.8
2 31.5” ? 33.8”
222.2 107.7
? 20.1 5 16.4
NOTE. Results are expressed as mean 2 SE; n = 12. “Significantly (P 5 0.05) different from corresponding basal values.
of gastric
duced inhibition time control
on the colonic (P >
0.05)
different
from
2).
of both
IV) did not affect the gastric
pg/kg
in control
conditions;
IV, it reduced
however,
emptying
10 minutes
U 50 488 (50 and 100 pg/kg emptying
of solids to normal
IV) restored values but had
no effect on the colonic distention-induced
delay in gas-
of liquids. (1 mg/kg
IV) had no effect on
and on the colonic distention-induced emptying
(Table
before fedototine
5). However,
(50 Kg/kg
restored the delay of gastric emptying distention
of liquids
before colonic
the gastric
10 minutes
of
at a dose of 100
emptying
distention,
tric emptying
solids
U 50 488 (10, 50, and
the gastric
(P 5 0.05). Given
delay on gastric
of gastric MMC because the MMC cycle
was not significantly (Table
distention-in-
emptying
100 pg/kg
gastric emptying it was inactive
the colonic distention-
4). Similarly,
Nor-BNI. Nor-BNI addition,
At a lower dose of 10 pg/
(Figure
significantly 108.6 * 17.7 108.2 ? 16.3
of liquids.
and liquids solids
of solids but
effect of colonic distention
did not influence
inhibition
with fedotoz-
the colonic disten-
of gastric emptying
had no effect on the inhibitory
Gastric MMC cycle (min)
Drugs
pretreatment
IV) eliminated
1331
(Table
injected
IV), nor-BNI
induced
by colonic
5).
Gastric Emptying Studies Colonic distention. Under the gastric
emptying
of solids
control
measured
conditions, 1 hour
feeding was 33.6% +- 9.9% (mean + SD; n = 12) of the initial weight of the solid phase, and the volume of liquid emptied During
was 25.8%
colonic
solids and liquids by 40.2%
+ 6.1% of the initial
distention,
volume.
below a painful
sensation
threshold,
lack of effect on behavior disrupt
the gastric
(P < 0.05) inhibited
used to distend
the colon
(Figure
much
respectively
of
4).
lower than
as suggested
MMC cycle without
of intestinal
emptying
distention by the
and heart rate, was enough
cyclic occurrence
the gastric
was significantly
and 24.8%,
We show that in fasted dogs, colonic
after
change
to
in the
MMC. The mean pressure (33.0
the pressure
+
5.4 mm
reported
Hg) was
to damage
the
Effect of fedotozine and U 50 488 on gastric emptying. When given at doses of lo- 100 l.tg/kg IV,
colonic wall (100 mL).21 It is also lower than the intralu-
fedotozine
in heart
did not affect the rate of gastric
50
emptying
of
minal
pressure
(49 mm Hg) known
rate and aortic
blood
1
TT
to cause an increase
pressure,
t lhlh ??
50
A
Vehicle (ml kg IV)
Fedolozine bon0 IV)
loo
u 50.480 tv91kg IV)
10
B
Vehicle (ml Ikg IV)
as previously
c
50
loo
u 50,486 b911cgIV)
4. Comparative influence of IV injection of fedotozine and U 50 488 on colonic distention-induced delay in gastric emptying of (A) colonic distention. *Significantly (P 5 0.05) different from corresponding basal solids and (13) liquids of a standard meal in dogs. 0, basal: value by Wilcoxon matched-pair signed-rank test. Results are means 2 SD; n = 12.
Rgure
GASTROENTEROLOGY Vol. 107, No. 5
1332 GUi ET AL.
reported
for the same species.22 Because it was recently
found that gastric motility layed in patients
with
and gastric emptying
IBS’ and because
are de-
50%-80%
of
gastric
these patients
have symptoms suggestive of disturbed emptying,23X24 this light colonic distention-in-
duced
inhibition
of gastric
model of the cologastric to pathophysiological vious studies motility
motility
may
problems
in patients
ferrets.12 Results
of the upper gut have been performed
study, the distention
was applied directly
colon via a cecostomy. relevant
Our method
to physiopathology
symptom
meal, was associated the colon, ascending
to distention
to the proximal
seems to be more a common
with the entry of digested
by breath et al.” observed
to distention
colon; also, an active muscular was evident
posed to a predominantly
food into
hydrogen concentrain humans that the
colon has a lesser resistance
the descending
by disten-
pain a few hours after a
as indicated
tion.25 Waldron
on the
In the present
of IBS, because
of IBS, lower-bowel
than
response
in the ascending
colon as op-
passive resistance
in the distal
colon.*’ The greater accommodation and active contractile response in the proximal colon would allow mixing and segmentation of large volumes of ileal effluent. Numerous hibitory
studies
testine.
Duodenal
reflexes elicited
distention
a vagally mediated, mediated inhibition
inhibition of vagal
increasing
activity
nation
have described
enterogastric
NANC
a vagal component
contributes
with IBS. Pre-
the presence
of in-
from the small in-
in dogs was shown to induce gastric relaxation.13
Neurally
of gastric tone may be produced excitatory, cholinergic neurons,
by by
in adrenergic neurons, or by a combiof these mechanisms. 12,28-30Youmans and Meak3
observed that distention of both the small intestine and colon induces an inhibition of gastric motility. It has been suggested that this response is a purely sympathetic
afferents
inhibiting
with the efferent
at least at two levels:
presynaptically on preganglionic vagal cholinergic fibers3’ and on myenteric cholinergic neurons.s2 However, by distention
distention
tion of the distal colon and/or the rectum.
by splanchnic
outflow
be a useful
reflex that possibly
of the effects of colonic
reflex mediated sympathetic
of the inhibition
of the intestines of the present
ionic distention-induced was eliminated hibits
vagally
of gastric
study show that the co-
inhibition
of gastric
by hexamethonium. mediated
gastric
ganglionic
tory cologastric
receptors
pathway.
distention-induced
motility
Hexamethonium relaxation
pig,33 which along with the present nicotinic
motility
was shown in anesthetized
study suggests
are involved
that
in the inhibi-
In anesthetized
inhibition
in-
in the guinea
rats, colonic
of gastric
motility
is
eliminated by bilateral cervical vagotomy and by hexamethonium,* suggesting that the efferent link of the cologastric
reflex is vagally
we are unable to ascertain
mediated.
whether
From our results,
the cologastric
observed are a vagovagal reflex or a spinovagal needs to be clarified in future experiments. The sympathetic ent study,
ganglionic
bretylium
tosylate,
reduce the inhibition
of gastric
blocker
reflexes
reflex; this
used in the pres-
failed to antagonize motility
induced
or to by co-
ionic distention, indicating that the cologastric reflex described is nonadrenergic. However, several studies34m36 have reported
that adrenergic
mechanisms
role in gastric relaxation
ulation
in the rat. It seems that the nonadrenergic
of the cologastric a part
reflex studied
of a physiological
than a pathophysiological stimulus.
induced
play an im-
portant
by painful
in the present
enterogastric
feedback
stimnature
study
is
rather
effect associated with a noxious
Our results show that U 50 488, a selective K-receptor agonist, and fedotozine act in the same manner to suppress the cologastric inhibitory reflex induced by colonic distention, suggesting that fedotozine acts through K
Table 5. Effect of Nor-BNI (1 mg/kg IV) on the Suppressive Effect of Fedotozine on Colonic Distention-Induced Gastric Emptying of Liquids and Solids of a Standard Meal in Dogs
Delay in
Gastric emptying (%)” Solid phase
Control Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV) After nor-BNI Saline (0.5 mL/kg IV) Fedotozine (50 pg/kg IV)
Liquid phase
Basal
Colonic distention
33.6 + 9.9 32.8 2 7.7
20.1 + 4.gb 32.3 5 5.9
25.8 2 6.1 26.5 -t 4.3
19.4 2 I.56 18.9 + 4.2b
35.1 k 8.2 33.9 2 7.2
23.3 2 2.2’ 17.4 k 2.gb
19.1 + 2.2b 20.9 + 3.9
15.1 + 2.1b 15.8 + 3.6’
“Measured 1 hour after the meal. %ignificantly (P 5 0.05) different from corresponding
basal values.
Basal
Colonic distention
November 1994
receptors.
FEDOTOZINE AND COLOGASTRIC REFLEX
This hypothesis
is supported
by the fact that
block
the gastric
response
to colonic
DAMGO, a selective p-receptor agonist, had no effect on the inhibitory influence of colonic distention on gastric
the postprandial state. Recently, that fedotozine acts on peripheral
motility.
modulates
Furthermore,
ine is blocked
the suppressive
by nor-BNI,
nist,37 and not by naltrindole,
gastric
acts through
motility
duces
colonic
efferents,
receptors
antagonist,
pressure
that in the previous
studies,
distention,
whereas
in the present induced
results
In the present solid
study,
to
speculated
of
related
it is
receptor duodenal
the inhibition occurred
This could explain
with granisetron.
we also show that
and liquid
phases
a painless
observed
in humans
during
painless
The effect of colonic distention
tying
of solids was eliminated
488;
however,
meal
with a delayed
in
rectal dis-
on gastric emp-
by fedotozine
the effect on the liquid
and U 50
phase was not
affected by either drug. Emptying of liquids is considered to depend on fundus and/or corpus contractions, whereas emptying
of solids is associated
with phasic contractions
of the corpus and antrum. The lack of effect of fedotozine and U 50 488 on the colonic distention-induced delay on gastric
emptying
fedotozine
may have a more
antrum during
to restore colonic
of the liquid a normal
distention.
U 50 488 and tifluadom,
phase suggests
pronounced gastric
K-Receptor administered
that
effect on the
emptying agonists,
of solids such as
at higher dosages
produce opposite effects on the gastric emptying of liquids and solids of a standard meal in dogs: they decrease the emptying rate of liquids while accelerating the emptying of solids.*’ We cannot exclude the possibility that, at the dosage used in this study, K-receptor agonists have no effect in the basal, unstimulated state but have an enhanced effect during colonic distention. The blocking
effect of fedotozine
that fedotozine
symptoms
on the colonic disten-
tion-induced delay in gastric emptying is eliminated by pretreatment with the K-receptor antagonist nor-BNI, suggesting that fedotozine acts through K receptors to
gastric
mo-
distention
gastric
motility
showed that patients
emptying,
it could be
or U 50 488 are able to relieve
in patients the present
colonic
with IBS. study shows that (1) a light
below painful in the fasted
sensation state
disrupts
and delays
the
gastric
emptying of a normal meal in dogs; (2) this cologastric reflex seems to be mediated through a cholinergic pathway involving through
nicotinic
adrenergic
ganglionic
pathway;
are able to block
duced inhibition site of action,
gastric
of the
still needs to be determined.
In conclusion,
fedotozine
of a standard
is in agreement
in the colonic distention-induced
tor inhibition
Because Van Wijk et al.’ recently
may induce a delay in gastric emptying
dogs; this result tention
5-HT,
to a painful
threshold.
obtained study,
colonic distention
However,
in the suppression
with IBS have a delay in gastric
that 5-HT3
by colonic distention
at a level below the painful
emptying
inhibition
in the response.
the response
of both
intragastric in urethane-
distention-induced
blocked
of gastric motility
re-
sheep,39 was unable
antagonists
the different
and
in awake dogs. This suggests
are not involved
worth noting
which
distention
rats18 or in awake the colonic
the hypothesis
distention.
receptor
in blood
gastric motility
has
6 or p receptors to restore normal
by duodenal
antagonize
that fedotozine
reflex in our study. However, the on sensory afferents or on motor
produced
anesthetized
We can hypothesize
inhibitory cologastric site of action, either
the decrease
pressure
the sensory afferents in the reversal of surgicalileus.
that
exclude
&receptor
induced
of action
a 5-HT,
a selective
antago-
the same mechanism
during
Granisetron,
K-receptor
during
Riviere et al.” showed K-opioid receptors and
an-
tagonist. 38 We can therefore fedotozine
effect of fedotoz-
a selective
distention
1333
transmission
and (3) K agonists the colonic
of gastric motility on afferent
or efferent
and not such as
distention-in-
and emptying. pathways,
Their remains
to be determined.
References 1. van Wijk HJ, Smout AJPM, Akkermans LMA, Roelofs JMM, ten Thije OJ. Gastric emptying and dyspeptic symptoms in the irritable bowel syndrome. Stand J Gastroenterol 1992;27:99-102. 2. Pearcy JF, Van Liere EJ. Studies on the visceral nervous system. Reflexes from the colon. Am J Physiol 1926; 78:57-64. 3. Youmans WM, Meak WJ. Reflex and humoral gastrointestinal inhibition in unanesthetized dogs during rectal stimulation. Am J Physiol 1937; 120:750-755. 4. Bojo L, Cassuto J. Gastric reflex relaxation by colonic distention. J Auton NeN Syst 1992; 38:57-64. 5. Jansson G. Vago-vagal reflex relaxation of the stomach in the cat. Acta Physiol Stand 1969; 75:245-252. 6. Zighelboim J, Talley NJ, Camilleri M and Phillips SF. Identification of a recta-gastric response in health using the barostat (abstr). Gastroenterology 1993; 104:A606. 7. Kellow JE, Gill RC, Wingate DL. Modulation of human upper gastrointestinal motility by rectal distension. Gut 1987;28:864868. 8. Youle M, Read NW. Effect of painless rectal distension on gastrointestinal transit of solid meal. Dig Dis Sci 1984;29:902-906. 9. Andrews PLR, Lawes INC. Interactions between splanchnic and vagus nerves in the control of mean intragastric pressure in the ferret. J Physiol 1984;351:473-490. 10. Abrahamsson H. Vagal relaxation of the stomach induced from the gastric antrum. Acta Physiol Stand 1973;89:406-414. 11. Abrahamsson H, Glise H, Glise K. Reflex suppression of gastric motility during laparotomy and gastroduodenal nociceptive stimulation. Stand J Gastroenterol 1979; 14:101-106. 12. Grundy D, Scratcherd T. A splanchno-vagal component of the inhibition of gastric motility by distension of the intestines. In:
1334
GIJC: ET AL.
Wienbeck M. ed. Motility of the digestive tract. New York: Raven, 1982:39-43. 13. De Ponti F, Azpiroz F, Malagelada JR. Reflex gastric relaxation in response to distension of the duodenum. Am J Physiol 1987; G595-G601. 14. Pascaud X, Honde C, Le Gallou B, Chanoine F, Roman F, B&no L, Junien JL. Effects of fedotozine on gastrointestinal motility in dogs: mechanism of action and related pharmacokinetics. J Pharm Pharmacol 1990;42:546-552. 15. Karaus M, Kittelman R, Lubke HJ, Erckenbrecht JF. Selective stimulation of phase 3 activity by fedotozine (JO 1196) in men (abstr). Gastroenterology 1990;98:A364. 16. Gue M, Junien JL, Pascaud X, B&no L. Antagonism of stressinduced gastric motor alteration and plasma cortisol release by fedotozine (JO 1196) in dogs. J Gastrointest Motil 1990; 2:258264. 17. Riviere PJM, Pascaud X, Chevalier E, Le Gallou B, Junien JL. Fedotozine reverses ileus induced by surgery or peritonitis: action at peripheral K-opioid receptors. Gastroenterology 1993; 104: 724-731. 18. Moss HE, Sanger GJ. The effects of granisetron, ICS 205-930 and ondansetron on the visceral pain reflex induced by duodenal distension. Br J Pharmacol 1990;100:497-501. 19. Pascaud X, Genton MJ, Bass P. A miniature transducer for recording intestinal motility in unrestrained chronic rats. Am J Physiol 1978; 235:E532-E529. 20. Gue M, Fioramonti J, B&no L. A simple double radiolabeled technique to evaluate gastric emptying of canned food meal in dogs: application to pharmacological tests. Gastroenterol Clin Biol 1988; 12:425-430. 21. Ness TJ, Gebhart GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res 1988;450:153169. 22. Cevese A, Mary DASG, Poltronieri R, Schena F, Vacca G. Haemodynamic effects of distension of the descending colon in anaesthetized dogs. J Physiol 1992;447:409-423. 23. Svendlund J, Sjodin I, Dotevall G, Gillberg R. Upper gastrointestinal and mental symptoms in the irritable bowel syndrome. Stand J Gastroenterol 1985;20:595-601. 24. Whorwell PJ, McCallum M, Reed FH, Roberts CT. Non-color features of irritable bowel syndrome. Gut 1986;27:37-40. 25. Cann PA, Read NW. A disease of the whole gut? In: Read NW, ed. Irritable bowel syndrome. London: Grune & Stratton 1985:53-63. 26. Waldron DJ, Gill RC, Bowes KL. Pressure response of human colon to intraluminal distension. Dig Dis Sci 1989;34:11631167. 27. Gill RC, Cote KR, Bowes KL, Kingma YJ. Human colonic smooth muscle: spontaneous contractile activity and response to stress. Gut 1986;27:1006-1013.
GASTROENTEROLOGY Vol. 107, No. 5
28. Grundy D, Salih AA, Scratcherd T. Modulation of vagal efferent fibre discharge by mechanoreceptors in the stomach, duodenum and colon of the ferret. J Physiol 1981; 319:43-52. 29. Grundy D, Scratcherd T. The role of the vagus and sympathetic nerves in the control of gastric motility. In: Akkermans LMA, Johnson AG, Read NW, eds. Gastric and gastroduodenal motility. New York: Praeger, 1984:21-33. 30. Roman C, Gonella J. Extrinsic control of digestive tract motility. In: Johnson LR, ed. Physiology of the digestive tract. New York: Raven, 1987:507-553. 31. Hirst GDS, McKirdy HC. A nervous mechanism for descending inhibition in guinea-pig small intestine. J Physiol (Lond) 1974; 238:129-144. 32. Jansson G, Martinson J. Studies on the ganglionic site of action of the sympathetic to the stomach. Acta Physiol Stand 1966; 68: 184-192. 33. Beani L, Bianchi C, Crema A. Vagal non-adrenergic inhibition of guinea pig stomach. J Physiol 1971;217:259-279. 34. Glise H, Lindhal BO, Abrahamsson H. Reflex adrenergic inhibition of gastric motility by nociceptive intestinal stimulation and peritoneal irritation in the cat. Stand J Gastroenterol 1980;15:673681. 35. Glise H, Abrahamsson H. Reflex vagal inhibition of gastric motility by intestinal nociceptive stimulation in the cat. Stand J Gastroenterol 1980; 15:769-774. 36. Bojo L, Cassuto J. Pain-induced inhibition of gastric tone is mediated by vagal non-adrenergic and by adrenergic reflexes. J Gastrointest Motil 1990;2:133-137. 37. Portoghese PS, Lipkowski AW, Takemori AE. Binaltorphimine and norbinaltorphimine. potent and selective K-opioid receptors antagonists. Life Sci 1987;40:1287-1292. 38. Portoghese PS, Sultana M, Takemori AE. Naltrindole, a highly selective and potent non-peptide opioid receptor antagonist. Eur J Pharmacol 1988;146:185-186. 39. Brikas P, Kania B, Fioramonti J, B&no L. Central and peripheral serotonergic influences on viscera-visceral inhibitory reflex during duodenal distention in sheep. Dig Dis Sci 1993; 38:1079-1086. 40. Gue M, Fioramonti J, Honde C, Pascaud X, Junien JL, Buena L. Opposite effects of K-opioid agonists on gastric emptying of liquids and solids in dogs. Gastroenterology 1989;95:927-931.
Received December 8, 1993. Accepted July 1, 1994. Address requests for reprints to: Michele Gue, Ph.D., Department of Pharmacology, lnstitut National de la Recherche Agronomique, 180, chemin de Tournefeuille, BP 3, 31931 Toulouse cedex, France. Fax: (31) 6128 53 10. Presented in part at the 1992 European Symposium of Gastrointestinal Motility and published in abstract form (1 Gastrointest Motil 1992;4:221). The authors thank MarieAnne Pilot for stylistic revision of the paper.
The ICAgonist Fedotozine Modulates Colonic DistentionInduced Inhibition of Gastric Motility and Emptying in Dogs MICHiLE
GUI?,*,’ JEAN LOUIS JUNIEN,* and LIONEL BUtNO+
*Institut de Recherche Jouveinal, Fresnes; and +Depattment of Pharmacology, lnstitut National de la Recherche Agronomique, Toulouse, France
Gastric motor disturbances, associated with a delay in gastric emptying, occur in patients with the irritable bowel syndrome. The influence of fedstozine and K agonists on the cologastric reflex produced by nonpainful colonic distention was evaluated in conscious dogs. Methods: Colonic distention was applied in dogs fitted with either strain gauges or gastric cannula to assess its influence on gastrointestinal motility and gastric emptying, respectively. Results: Colonic distention delayed the occurrence of gastric migrating motor complex by 141%, an effect blocked by intravenous fedotozine, U 50 488 (25 and 50 ug/ kg), and hexamethonium (0.5 mg/kg) but not by PAla’, #methyl, Phe4, Gly5-ol enkephalin (1, 5, and 10 ug/ kg), granisetron (50 and 100 pg/kg), or bretylium to sylate (5 mg/kg). Nor-binaltorphimine hydrochloride (1 mg/kg intravenously) eliminated the suppressive action of fedotozine. Colonic distention reduced the lhour gastric emptying of solids by 40.1%, an effect blocked by fedotozine and U 50 488 (50 and 100 ug/ kg); nor-binaltorphimine hydrochloride (1 mg/kg) antagonized the blocking effect of fedotozine. Conclusions: Fedotozine acts through K receptors to block the colonic distention-induced delay on gastric motility and emptying. The cologastric reflex involves nicotinic ganglionic receptors but not adrenergic pathway and 5hydroxytryptamine 3 receptors. Backg~~nd/Aims:
M
otility disorders in different parts of the gastroin-
testinal tract have been implicated in various functional bowel disorders, such as the irritable bowel syndrome (IBS). Gastric motor disturbances, associated with a delay in gastric emptying, have been described recently in IBS’ and may result from an inhibitory reflex originating in the colon. Numerous studies have shown that distention of the colon or the rectum induces a decrease in gastric motility in dogs,2*3 rats,4 cats,’ and humans.6 Other studies in human volunteers showed that painless rectal distention induced inhibition of postprandial gastric contractions’ and gastric emptying.’ Neurally mediated gastric motor inhibition may be caused by an inhibition of cholinergic excitation, adrenergic stimulation, or
nonadrenergic, noncholinergic (NANC) inhibition.” The cologastric
inhibitory
sympathetic
reflex was reported to have both
and vagal
components.
Abrahamson
et
al. “J* showed that NANC vagal efferents are involved in the inhibition of gastric motility in response to noxious stimuli and suggest that these efferents are excited by distention
of the colon.12 Duodenal distention
in dogs
induced a vagally mediated NANC gastric relaxation.13 Fedotozine is a new compound acting peripherally as an agonist on K-opioid receptors.14*‘5 Fedotozine restores the gastric migrating
motor complex (MMC) inhibited
by acoustic stress in dogs16 and suppresses the surgical ileus-induced
intestinal
motor
inhibition
in
rats
through peripheral K receptors.” The aims of this study were to develop a model of nonpainful prolonged distention
of the proximal colon
in awake dogs to determine the effect of distention on gastrointestinal motility in the fasted state and on gastric emptying of a standard nutrient meal and to determine the involvement of cholinergic and/or adrenergic pathways on the viscerovisceral reflex. Additionally, we aimed to evaluate the influence of fedotozine on the cologastric inhibitory reflex on motility and gastric emptying and to determine its mechanism of action by comparing its effect with those of U 50 488 (a K agonist) and D-Ala2, N-methyl-Phe4-, Gly5-01 ekephalin (DAMGO) (a p-receptor agonist). Because it has been reported recently that 5-hydroxytryptamine 3 (5-HT3) receptor antagonists reduce the gastric response to duodenal distention,18 granisetron was also tested.
Materials and Yethads Animal Preparation Gastrointestinal motility. Six adult beagle dogs weighing lo- 13 kg were used. Under halothane (Fluothane Abbnwiations used in this paper: DAMGO, BAla’, Nmethyl, Phe4, Gly%l enkephalln; IHTI, 5hydroxytryptamine 3; IGS, irritable bowel syndrome; NANC, nonadrenerglc, nonchollnerglc; MMC, mlgratlng motor complex; norBNI, nor-blnaltorphlmlne hydrochloride. 0 1994 by the American Gastroenterological Association 00165085/94/$3.OC
1328
ND, and
GASTROENTEROLOGY Vol. 107, No. 5
GUE ET AL.
Coopers,
Maux) anesthesia,
a cecostomy
Llmll
was performed
PIWSSU~
two strain-gauge
method
transducers were implanted using a described, l9 one on the stomach 7 cm from
previously
the pylorus and the other on the proximal the ligament
of Treitz.
subcutaneously allowed
of canned
60 cm from
wires were brought
to the back of the neck, and the animals
15 days to recover before beginning
Each day at 5 21.7%
jejunum
The strain-gauge
PM,
food (Fido-Quaker,
dry matter,
Bordeaux,
7.7%
protein,
drates, and 2.6% minerals.
Water
Gastric
emptying. Four
weighing
lo-12
a Thomas
cannula
fat, 6.9%
male
beagle
adult halothane
was placed on the greater
on the left abdominal mals were allowed
to recover for 2 weeks before tests.
Motility recordings. Gastrointestinal
gauge was calibrated clamped
firmly
in a horizontal
strain gauge, and weights from the soldering
point.
the first recording
session,
ages were applied to calibrate kadenki,
1 mm lateral
(in millivolts)
curve was calculated. direct
was Before
current
the potentiometric
volt-
recorder (Ri-
of 400 g of canned
France) containing
food (Rox, Quaker,
21.7% dry matter,
4.5% fat, 6.9% carbohydrates,
7.7% protein,
and 2.6% minerals
from sheep intravenously
10 PCi [57Co]cyanocobalamine act, 10 l.HXpg) consisted
and killed
beled with 0.5 PCi [‘*C]PEG
(NEN
with
measured.
phase
water marker, Products,
after determination of five samples
(4-5
scintillation
contents
Bos-
eating,
was performed
1
were homogenized
taken; each sample of
and 57Co was counted
(SL 40; Intertechnique,
France). The rate of gastric emptying calculated
from these measurements
120
was performed
for each animal,
the balloon
increments
to a maxi-
The threshold
was reached when the animals showed
(contractions
of the abdomen,
lying on the
accompanied
by an increase
of at least 15% in heart rate. The compliance
of the balloon
before the experiments
by inflating
1). The balloon had a negligible
inside the colon represented the resistance the occurrence plied
the balloon
resistance,
especially the experi-
the intracolonic
pressure
and not
of the balloon. motility
of a gastric
for 90 minutes. was applied
studies,
40-50
MMC, colonic
For gastric immediately
dard meal and maintained
using
a
Plaisir,
of liquids and solids was as previously
described.”
ments, injection
and volume. Two series
mL) were rapidly
system
110
into the colon via the cecos-
the threshold
For gastrointestinal
la-
gamma counter (MR 252; Kontron, Basel, Switzerland). The second series was prepared for [‘*C]PEG determination using a liquid
100
minutes
distention
emptying
studies,
after ingestion
after
was apcolonic
of a stan-
for 1 hour, after which the gastric
were collected. Gastrointestinal motility. In the first series of experi-
contents
of the total weight
the first series was weighed,
inserted
floor, and sniffing the cecostomy),
minutes.
hour after the meal. The collected
90
mum of 120 mL. The balloon pressure and the heart rate were
contents
of the gastric
80
Procedure
balloon
tomy. To evaluate
‘*C; the meal was given to the animals for spontaneous collection
70 (ml)
was filled with water (37°C) by lo-mL
distention
Total
60
Colonic distention. Colonic distention using a lo-cm
ton, MA; sp act, 1 pCi/mg). The liquid phase was mixed with the solid phase after sampling 0.S mL for determination of which did not exceed 2-3
50
ments; we therefore assumed that the balloon pressure recorded
50 mg of polyeth-
Research
40
at 60 mL, which was the volume used throughout
Paris, France; sp
24 hours later. The liquid a nonabsorbable
30
Experimental
(Figure
Labeled
(IV) injected
(Amersham,
of 100 mL of tap water containing
ylene glycol (PEG) 4000,
20
means + SD; n = 12. A, mean intraballoon pressure for a volume of 60 mL. Dotted vertical lines indicate the lowest volumes at which heart rate changes and discomfort were observed. Note that for a volume of 60 mL, the resistance of the balloon is negligible and that the intraballoon pressure is equivalent to the intracolonic pressure.
was assessed
mixed with
sheep liver (20 g) labeled with [“Co]cyanocobalamine. liver was obtained
10
signs of discomfort
Determination of gastric emptying. The solid phase Bordeaux,
I
(+) or inserted into the proximal colon of dogs (l3). Results are
was
Tokyo, Japan).
of the meal consisted
0
at the level of the
corresponding
,
’
Each strain
The transducer
The amplitude
I
bridge ampli-
recorder.
(1 - 5 g) were attached
noted, and an average calibration
ac-
by connecting
Wheatstone
position
-
Figure 1. Changes in pressure vs. volume of balloon on the bench
The ani-
mechanical
23 hours/day
before implantation.
30
of the
It was exteriorized
was also performed.
fier (Vishay, France) and a potentiometric
_
Volume
wall 5 cm from the last rib and 10 cm
the strain gauges to a four-channel
40
anesthesia,
A cecostomy
continuously
_
dogs
curvature
from the midline.
tivity was recorded
50
carbohy-
ad libitum.
gastric body about 10 cm from the pylorus.
-
containing
was available
kg were used. Under
60
of hami rate changs
meal of 500 g
France),
4.5%
-
were
the experiments.
the dogs received a standard
70
OmW)
colonic
distention
was preceded
(10 minutes)
of vehicle (saline) alone or with fedotozine
by IV (10, 25,
or 50 pg/kg), U 50 488 (10, 25, or 50 yg/kg), or DAMGO (1, 5, or 10 pg/kg). In a second series of experiments, norbinaltorphimine hydrochloride (nor-BNI; 1 mg/kg), a specific K-receptor antagonist, or naltrindole, a specific a-receptor antagonist (100 pg/kg), were injected IV 10 minutes before fedotozine (50 p/kg IV). Colonic distention was performed 10 minutes after the last IV injection as in the first series of experiments. In a third series of experiments, to evaluate a
November 1994
FEDOTOZINE AND COLOGASTRIC REFLEX
The protocols
Table 1. Influence of Fedotozine on Maximum and Minimum lntracolonic Pressures pressure (mm Hg)
lntracolonic
Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV)
mentation
were approved
Committee
Maximum pressure
Minimum pressure
34.2 k 3.8 34.8 2 4.3
10.2 + 4.3 10.7 k 3.8
Evaluation The
lowest
ally detectable increase
of Pain Threshold pressure
thresholds
were performed
in dogs receiving
an IV injection
90 and
100 mL, respectively
alone (control) or saline with fedotozine
(50 pg/kg);
was filled with warm water (37°C) by lo-mL maximum
of 120 mL. In a fourth
antagonist; nicotinic
50 and 100 pg/kg), blocking
sympathetic istered
hexamethonium
ganglionic
blocking
IV 10 minutes
Each treatment
to a
agent, 5 mg/kg)
(n = 12 experiments)
(a
were assessed by measuring of the MMC pattern. SD and were compared
Motor
of gastric
of variance
mechanical
disruption as means
+
and paired
t
gastric
activity
fedototine
of vehicle alone or vehicle
or U 50 488 (10, 50, and
before
feeding.
Immediately
test meal, the colon was distended experiments. which
The distention
the gastric
of experiments,
contents
nor-BNI
before fedotozine
were collected.
series. Each treatment
was performed
was performed
for a P value I
Compounds. The fedotozine,
in triplicate
using a Wilcoxon
0.05. Results
following
U 50 488, and nor-BNI
analysis
matched-pair significant
as mean -f: SD.
compounds were synthesized
were
injected or gastric
All drugs
at doses that had no effect on gastrointestinal emptying.
the whole distention
Colonic
for 20 hours,
occurring distention
MMC continued
3). Compliance
the control
at 113.4
+ 18.6-minute
(60 mL) delayed MMC
by 141%,
at a normal
curves indicated
antral
by cyclic phases of the occurwhereas
frequency
that for a volume
the
(Figure of 6O-
mL, colonic pressure was 33.0 ? 5.4 mm Hg (Figure 1). The time interval between the first and second gastric MMC after colonic distention
was not significantly
ent (P > 0.05) from the control
interval.
differ-
No difference
used:
2
d 2 t t
30
P
by Jouve-
France). in saline.
its never
test meal
tron was a gift by SK Beecham (Paris, France); and naltrindole was purchased from Sigma Chimie (St. Quentin Fallavier, were dissolved
and the balloon pressure
series
inal (Fresnes, France); hexamethonium, bretylium tosylate, and DAMGO were purchased from RBI (Illkirch, France); granise-
All compounds
of 60 mL. during
in each dog
were considered
are expressed
of the colon
90
as in the previous
of animals,* statistical
test, and differences
with a volume
the
during
10 minutes
order.
Because of the small number signed-rank
In a second
IV), and the radiolabeled
after the last injection
of the results
for 1 hour, after
(1 mg/kg IV) was injected
(50 pg/kg
10
of the
as in the first part of the
was given 10 minutes in a randomized
100 pg/kg)
after ingestion
was maintained
pressure
was characterized
contractions
intervals. jejunal
Gastric emptying. In the first series of experiments,
minutes
adap-
we recorded
Studies
rence of the next gastric
the dogs were given an IV injection
used was 35 % a putative
1).
In dogs fasted
effects
test.
with
distention
of
were admin-
are expressed
by analysis
balloon
by the balloon,
Motility
order.
the duration
The values
of colonic
time (Table
twice in each of the six dogs
in a randomized
of balloon
exceeded 34.2 + 3.8 mm Hg during
tosylate
before colonic distention.
was applied
minimum
k 7.2
1). Consequently,
To evaluate
was no accommodation
distention
(5-HT,
(ganglionic
or bretylium
There
(Figure
the volume
0.05)
to a volume
of the colon to distention, and
minutes
the balloon
increments
series, granisetron
agent, 0.5 mg/kg),
maximum
of saline
(P 5
in heart rate for the six dogs were 44.8
and 50.2 + 5.9 mm Hg, corresponding
tive reaction
curves
for visu-
recorded
and significant
40% below the threshold. on colonic tone, compliance
9 137 and 9208).
(agreements
discomfort
in all experiments,
effect of fedotozine
Experi-
Results
NOTE. Results are expressed as mean + SD (n = 12) during 90 minutes of colonic distention with a balloon filled with 60 mL of warm water (37°C).
possible
by the Midi-Pyre&es
1329
were
motility
0,x 0
. SlO
ib
l&l
VOLUME (ml) flgure 2. Influence of intravenous injection of fedotozine ( + ; 50 ug/ kg) and vehicle (m; 0.1 mL/kg) on intracolonic pressure response to increasing volumes of distention in fasted dogs. Results are expressed as mean k SD; n = 12. *P > 0.05.
GASTROENTEROLOGY Vol. 107, No. 5
GUE ET AL.
1330
Table 2. Effect of 5-HT3 Receptor Antagonist and Ganglionic Blockers on Colonic Distention-induced Gastric MMC Cycle
Table 3. Effects of Fedotozine, U 50 488, and DAMGO on Colonic Distention-Induced MMC in Fasted Dogs
Delay in
Gastric MMC cycle (min)
inhibition of Gastric
Gastric MMC cycle (min)
Drugs
Basal
Colonic distention
Drugs
Basal
Vehicle Hexamethonium 0.5 mg/kg IV Bretylium 5 mg/kg IV Granisetron 50 fig/kg IV 100 r.lg/kg IV
100.4 * 17.3
236.6 ? 26.6a
96.9 2 13.7
119.3 -c 30.8
130.8 ? 33.5
113.3 It 18.4
232.3 2 24.7”
103.4 rt 26.2 121.6 ? 44.3
241.7 + 34.3” 250.6 -c 27.8”
Saline (0.5 mL/kg IV) Fedotozine @g/kg IV) 10 25 50 U 50 488 (/&& /l’) 10 25 50 DAMGO @g/kg IV) 1 5 10
NOTE. Results are expressed as mean -t SE; n = 12. “Significantly (P 5 0.05) different from corresponding basal values.
in gastric viously
response
was observed
between
naive and pre-
tested dogs. Bretylium tosylate and hexamethonium.
methonium
(0.5 mg/kg
MMC duration
IV) did not modify
(Table 2) but prevented
tention-induced
inhibition
26.6 minutes tosylate
(5 mg/kg
Bretylium
IV) had no effect on gastric
cycle and did not affect (P > 0.05) the colonic tion-induced
lengthening
Fedotozine, U 50 488,
and DAMGO. When
did not affect the duration
cycle significantly
fedotozine
in-
229.4 5 29.5" 124.9 2 15.3 103.9 lr 9.9
105.3 2 15.7 97.0 ? 10.6 110.3 5 21.6
215.1 -c 28.4” 132.8 2 35.4 124.9 + 22.3
99.4 2 10.5 94.6 ? 23.2 92.5 * 12.2
201.9 + 25.1” 198.7 + 19.0” 211.6 -c 26.8”
mg/kg IV, nor-BNI had no effect on gastrointestinal motility and on colonic distention-induced gastric motor
inhibition
10 minutes
(Table
4). However,
administered
10
minutes before fedotozine (50 pg/kg IV), nor-BNI eliminated the inhibitory action of fedotozine on colonic distention-induced 4). In contrast,
inhibition naltrindole
the blocking
distention-induced Granisetron.
in fasted dogs,
of the gastric MMC
(P > 0.05). Injected
111.5 2 20.2 106.4 2 20.8 108.1 -c 20.9
NOTE. Results are expressed as mean ? SD; n = 12 assays. “Significantly (P 5 0.05) different from corresponding basal values.
to eliminate
(Table 2).
jected at IV doses of 25 and 50 pg/kg
colonic distention,
MMC disten-
of gastric MMC cycle (232.3 ?
24.7 vs. 236.6 ? 26.6 minutes)
fedotozine
(MMC
with 236.6 +
with control colonic distention).
+ 24.3”
the gastric
motility
compared
233.9
Hexa-
the colonic dis-
of gastric
cycle of 130.8 + 33.5 minutes
Colonic distention
pg/kg
of gastric
(100 pg/kg
MMC
IV) was unable
effect of fedotozine
gastric motor disturbance Granisetron
injected
IV had no effect on gastrointestinal
(Table
on colonic (Table 4).
at 50 and 100 motility;
in
before
(25 and 50 pg/kg IV) elim-
inated the colonic distention-induced
lengthening
of the
gastric MMC cycle (Table 3 and Figure 3). However, at a lower dose (10 pg/kg), fedotozine did not reduce the colonic distention-induced ble 3). Injected IV at 50 pg/kg,
gastric
motor
which prevented
changes
(Ta-
the effects
of colonic distention on the gastric MMC, fedotozine had no effect (P > 0.05) on the compliance curve compared with control (Figure 2). U 50 488 (25 and 50 pg/kg IV) also suppressed (P < 0.05) the inhibition of gastric MMC induced by colonic distention (Table 3 and Figure 3). At a lower dose, U 50 488 (10 Fg/kg IV) had no effect on colonic distentioninduced gastric motor inhibition (Table 3). In contrast, DAMGO (1, 5, and 10 pg/kg IV) had no effect on colonic distention-induced inhibition of gastric motility (Table 3). Nor-BNI and naltrindole. Injected at a dose of 1
Figure 3. Blockade of colonic distention-induced inhibition of gastric MMC by fedotozine and U 50 488 in fasted dogs. Note that colonic distention selectively delayed the occurrence of the gastric but not the jejunal MMC.
November 1994
FEDOTOZINE AND COLOGASTRIC REFLEX
Table 4. Effect of Nor-BNI and Naltrindole on Disinhibition by Fedotozine on Colonic Distention-induced Gastric Motor Inhibition
solids and liquids.
However,
ine (50 and 100 pg/kg tion-induced
reduction
on gastric emptying Colonic distention
Basal
kg, fedotozine induced
Control Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV) After nor-BNI Saline (0.5 mL/kg IV) Fedotozine (50 ug/kg IV) After naltrindole Saline (0.5 mL/kg IV) Fedotozine (50 f&!/kg IV)
96.9 ? 13.7 108.1 t 20.9
233.9 103.9
+ 24.3” 2 9.9
112.3 2 23.4 91.3 * 11.7
239.7 225.8
2 31.5” ? 33.8”
222.2 107.7
? 20.1 5 16.4
NOTE. Results are expressed as mean 2 SE; n = 12. “Significantly (P 5 0.05) different from corresponding basal values.
of gastric
duced inhibition time control
on the colonic (P >
0.05)
different
from
2).
of both
IV) did not affect the gastric
pg/kg
in control
conditions;
IV, it reduced
however,
emptying
10 minutes
U 50 488 (50 and 100 pg/kg emptying
of solids to normal
IV) restored values but had
no effect on the colonic distention-induced
delay in gas-
of liquids. (1 mg/kg
IV) had no effect on
and on the colonic distention-induced emptying
(Table
before fedototine
5). However,
(50 Kg/kg
restored the delay of gastric emptying distention
of liquids
before colonic
the gastric
10 minutes
of
at a dose of 100
emptying
distention,
tric emptying
solids
U 50 488 (10, 50, and
the gastric
(P 5 0.05). Given
delay on gastric
of gastric MMC because the MMC cycle
was not significantly (Table
distention-in-
emptying
100 pg/kg
gastric emptying it was inactive
the colonic distention-
4). Similarly,
Nor-BNI. Nor-BNI addition,
At a lower dose of 10 pg/
(Figure
significantly 108.6 * 17.7 108.2 ? 16.3
of liquids.
and liquids solids
of solids but
effect of colonic distention
did not influence
inhibition
with fedotoz-
the colonic disten-
of gastric emptying
had no effect on the inhibitory
Gastric MMC cycle (min)
Drugs
pretreatment
IV) eliminated
1331
(Table
injected
IV), nor-BNI
induced
by colonic
5).
Gastric Emptying Studies Colonic distention. Under the gastric
emptying
of solids
control
measured
conditions, 1 hour
feeding was 33.6% +- 9.9% (mean + SD; n = 12) of the initial weight of the solid phase, and the volume of liquid emptied During
was 25.8%
colonic
solids and liquids by 40.2%
+ 6.1% of the initial
distention,
volume.
below a painful
sensation
threshold,
lack of effect on behavior disrupt
the gastric
(P < 0.05) inhibited
used to distend
the colon
(Figure
much
respectively
of
4).
lower than
as suggested
MMC cycle without
of intestinal
emptying
distention by the
and heart rate, was enough
cyclic occurrence
the gastric
was significantly
and 24.8%,
We show that in fasted dogs, colonic
after
change
to
in the
MMC. The mean pressure (33.0
the pressure
+
5.4 mm
reported
Hg) was
to damage
the
Effect of fedotozine and U 50 488 on gastric emptying. When given at doses of lo- 100 l.tg/kg IV,
colonic wall (100 mL).21 It is also lower than the intralu-
fedotozine
in heart
did not affect the rate of gastric
50
emptying
of
minal
pressure
(49 mm Hg) known
rate and aortic
blood
1
TT
to cause an increase
pressure,
t lhlh ??
50
A
Vehicle (ml kg IV)
Fedolozine bon0 IV)
loo
u 50.480 tv91kg IV)
10
B
Vehicle (ml Ikg IV)
as previously
c
50
loo
u 50,486 b911cgIV)
4. Comparative influence of IV injection of fedotozine and U 50 488 on colonic distention-induced delay in gastric emptying of (A) colonic distention. *Significantly (P 5 0.05) different from corresponding basal solids and (13) liquids of a standard meal in dogs. 0, basal: value by Wilcoxon matched-pair signed-rank test. Results are means 2 SD; n = 12.
Rgure
GASTROENTEROLOGY Vol. 107, No. 5
1332 GUi ET AL.
reported
for the same species.22 Because it was recently
found that gastric motility layed in patients
with
and gastric emptying
IBS’ and because
are de-
50%-80%
of
gastric
these patients
have symptoms suggestive of disturbed emptying,23X24 this light colonic distention-in-
duced
inhibition
of gastric
model of the cologastric to pathophysiological vious studies motility
motility
may
problems
in patients
ferrets.12 Results
of the upper gut have been performed
study, the distention
was applied directly
colon via a cecostomy. relevant
Our method
to physiopathology
symptom
meal, was associated the colon, ascending
to distention
to the proximal
seems to be more a common
with the entry of digested
by breath et al.” observed
to distention
colon; also, an active muscular was evident
posed to a predominantly
food into
hydrogen concentrain humans that the
colon has a lesser resistance
the descending
by disten-
pain a few hours after a
as indicated
tion.25 Waldron
on the
In the present
of IBS, because
of IBS, lower-bowel
than
response
in the ascending
colon as op-
passive resistance
in the distal
colon.*’ The greater accommodation and active contractile response in the proximal colon would allow mixing and segmentation of large volumes of ileal effluent. Numerous hibitory
studies
testine.
Duodenal
reflexes elicited
distention
a vagally mediated, mediated inhibition
inhibition of vagal
increasing
activity
nation
have described
enterogastric
NANC
a vagal component
contributes
with IBS. Pre-
the presence
of in-
from the small in-
in dogs was shown to induce gastric relaxation.13
Neurally
of gastric tone may be produced excitatory, cholinergic neurons,
by by
in adrenergic neurons, or by a combiof these mechanisms. 12,28-30Youmans and Meak3
observed that distention of both the small intestine and colon induces an inhibition of gastric motility. It has been suggested that this response is a purely sympathetic
afferents
inhibiting
with the efferent
at least at two levels:
presynaptically on preganglionic vagal cholinergic fibers3’ and on myenteric cholinergic neurons.s2 However, by distention
distention
tion of the distal colon and/or the rectum.
by splanchnic
outflow
be a useful
reflex that possibly
of the effects of colonic
reflex mediated sympathetic
of the inhibition
of the intestines of the present
ionic distention-induced was eliminated hibits
vagally
of gastric
study show that the co-
inhibition
of gastric
by hexamethonium. mediated
gastric
ganglionic
tory cologastric
receptors
pathway.
distention-induced
motility
Hexamethonium relaxation
pig,33 which along with the present nicotinic
motility
was shown in anesthetized
study suggests
are involved
that
in the inhibi-
In anesthetized
inhibition
in-
in the guinea
rats, colonic
of gastric
motility
is
eliminated by bilateral cervical vagotomy and by hexamethonium,* suggesting that the efferent link of the cologastric
reflex is vagally
we are unable to ascertain
mediated.
whether
From our results,
the cologastric
observed are a vagovagal reflex or a spinovagal needs to be clarified in future experiments. The sympathetic ent study,
ganglionic
bretylium
tosylate,
reduce the inhibition
of gastric
blocker
reflexes
reflex; this
used in the pres-
failed to antagonize motility
induced
or to by co-
ionic distention, indicating that the cologastric reflex described is nonadrenergic. However, several studies34m36 have reported
that adrenergic
mechanisms
role in gastric relaxation
ulation
in the rat. It seems that the nonadrenergic
of the cologastric a part
reflex studied
of a physiological
than a pathophysiological stimulus.
induced
play an im-
portant
by painful
in the present
enterogastric
feedback
stimnature
study
is
rather
effect associated with a noxious
Our results show that U 50 488, a selective K-receptor agonist, and fedotozine act in the same manner to suppress the cologastric inhibitory reflex induced by colonic distention, suggesting that fedotozine acts through K
Table 5. Effect of Nor-BNI (1 mg/kg IV) on the Suppressive Effect of Fedotozine on Colonic Distention-Induced Gastric Emptying of Liquids and Solids of a Standard Meal in Dogs
Delay in
Gastric emptying (%)” Solid phase
Control Saline (0.5 ml/kg IV) Fedotozine (50 pg/kg IV) After nor-BNI Saline (0.5 mL/kg IV) Fedotozine (50 pg/kg IV)
Liquid phase
Basal
Colonic distention
33.6 + 9.9 32.8 2 7.7
20.1 + 4.gb 32.3 5 5.9
25.8 2 6.1 26.5 -t 4.3
19.4 2 I.56 18.9 + 4.2b
35.1 k 8.2 33.9 2 7.2
23.3 2 2.2’ 17.4 k 2.gb
19.1 + 2.2b 20.9 + 3.9
15.1 + 2.1b 15.8 + 3.6’
“Measured 1 hour after the meal. %ignificantly (P 5 0.05) different from corresponding
basal values.
Basal
Colonic distention
November 1994
receptors.
FEDOTOZINE AND COLOGASTRIC REFLEX
This hypothesis
is supported
by the fact that
block
the gastric
response
to colonic
DAMGO, a selective p-receptor agonist, had no effect on the inhibitory influence of colonic distention on gastric
the postprandial state. Recently, that fedotozine acts on peripheral
motility.
modulates
Furthermore,
ine is blocked
the suppressive
by nor-BNI,
nist,37 and not by naltrindole,
gastric
acts through
motility
duces
colonic
efferents,
receptors
antagonist,
pressure
that in the previous
studies,
distention,
whereas
in the present induced
results
In the present solid
study,
to
speculated
of
related
it is
receptor duodenal
the inhibition occurred
This could explain
with granisetron.
we also show that
and liquid
phases
a painless
observed
in humans
during
painless
The effect of colonic distention
tying
of solids was eliminated
488;
however,
meal
with a delayed
in
rectal dis-
on gastric emp-
by fedotozine
the effect on the liquid
and U 50
phase was not
affected by either drug. Emptying of liquids is considered to depend on fundus and/or corpus contractions, whereas emptying
of solids is associated
with phasic contractions
of the corpus and antrum. The lack of effect of fedotozine and U 50 488 on the colonic distention-induced delay on gastric
emptying
fedotozine
may have a more
antrum during
to restore colonic
of the liquid a normal
distention.
U 50 488 and tifluadom,
phase suggests
pronounced gastric
K-Receptor administered
that
effect on the
emptying agonists,
of solids such as
at higher dosages
produce opposite effects on the gastric emptying of liquids and solids of a standard meal in dogs: they decrease the emptying rate of liquids while accelerating the emptying of solids.*’ We cannot exclude the possibility that, at the dosage used in this study, K-receptor agonists have no effect in the basal, unstimulated state but have an enhanced effect during colonic distention. The blocking
effect of fedotozine
that fedotozine
symptoms
on the colonic disten-
tion-induced delay in gastric emptying is eliminated by pretreatment with the K-receptor antagonist nor-BNI, suggesting that fedotozine acts through K receptors to
gastric
mo-
distention
gastric
motility
showed that patients
emptying,
it could be
or U 50 488 are able to relieve
in patients the present
colonic
with IBS. study shows that (1) a light
below painful in the fasted
sensation state
disrupts
and delays
the
gastric
emptying of a normal meal in dogs; (2) this cologastric reflex seems to be mediated through a cholinergic pathway involving through
nicotinic
adrenergic
ganglionic
pathway;
are able to block
duced inhibition site of action,
gastric
of the
still needs to be determined.
In conclusion,
fedotozine
of a standard
is in agreement
in the colonic distention-induced
tor inhibition
Because Van Wijk et al.’ recently
may induce a delay in gastric emptying
dogs; this result tention
5-HT,
to a painful
threshold.
obtained study,
colonic distention
However,
in the suppression
with IBS have a delay in gastric
that 5-HT3
by colonic distention
at a level below the painful
emptying
inhibition
in the response.
the response
of both
intragastric in urethane-
distention-induced
blocked
of gastric motility
re-
sheep,39 was unable
antagonists
the different
and
in awake dogs. This suggests
are not involved
worth noting
which
distention
rats18 or in awake the colonic
the hypothesis
distention.
receptor
in blood
gastric motility
has
6 or p receptors to restore normal
by duodenal
antagonize
that fedotozine
reflex in our study. However, the on sensory afferents or on motor
produced
anesthetized
We can hypothesize
inhibitory cologastric site of action, either
the decrease
pressure
the sensory afferents in the reversal of surgicalileus.
that
exclude
&receptor
induced
of action
a 5-HT,
a selective
antago-
the same mechanism
during
Granisetron,
K-receptor
during
Riviere et al.” showed K-opioid receptors and
an-
tagonist. 38 We can therefore fedotozine
effect of fedotoz-
a selective
distention
1333
transmission
and (3) K agonists the colonic
of gastric motility on afferent
or efferent
and not such as
distention-in-
and emptying. pathways,
Their remains
to be determined.
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Received December 8, 1993. Accepted July 1, 1994. Address requests for reprints to: Michele Gue, Ph.D., Department of Pharmacology, lnstitut National de la Recherche Agronomique, 180, chemin de Tournefeuille, BP 3, 31931 Toulouse cedex, France. Fax: (31) 6128 53 10. Presented in part at the 1992 European Symposium of Gastrointestinal Motility and published in abstract form (1 Gastrointest Motil 1992;4:221). The authors thank MarieAnne Pilot for stylistic revision of the paper.