Effects of rectal distensions on nociceptive flexion reflexes
in humans
Didier
Bouhassira1,
Jean-Marc
Sabaté2,
Benoit
Coffin2,
Daniel
Le
Bars1,
Jean-Claude
Willer3, and
Raymond
Jian2
1 Institut National de la
Santé et de la Recherche Médicale U-161, 75014 Paris;
2 Department of
Gastroenterology and Institut National de la Santé et de la
Recherche Médicale U-290, Saint-Louis and Saint-Lazare Hospitals,
75009 Paris; and 3 Neurophysiology
Laboratory, Pitié-Salpêtrière Hospital, 75013 Paris, France
 |
ABSTRACT |
We previously showed that gastric distension
inhibits the somatic nociceptive flexion RIII reflex. To
explore further the viscerosomatic interactions, we tested in the
present study the effects of rectal distensions on RIII reflexes. Rapid
and slow-ramp rectal distensions were performed in 10 healthy
volunteers with an electronic barostat. The RIII reflex was
continuously recorded from the lower limb during both types of
distension and from the upper limb during rapid distensions. The
visceral sensations were scored on a graded questionnaire. Rapid
distensions facilitated the RIII reflex recorded from the lower limb,
but at the highest distension level, facilitation was followed by
inhibition. Slow-ramp distension induced gradual inhibition of the RIII
reflex, which correlated with both distension volume and visceral
sensation. RIII reflex recorded from the upper limb was also inhibited
by rapid rectal distensions. Reflex inhibitions were probably related to the activation of pain modulation systems. One plausible explanation for the facilitatory effects, observed only at the lower limb, is the
convergence of rectal and reflex afferents at the same levels of the
spinal cord. The differential effects of rapid and slow-ramp
distensions suggest the activation of two distinct populations of
mechanoreceptors by these two modes of distension.
pain; nociception; visceral perception; sensory
pathways
 |
INTRODUCTION |
THE OBSERVATION THAT patients with functional
intestinal disorders, such as nonulcer dyspepsia, noncardiac chest
pain, or irritable bowel syndrome, have a lowered threshold for
discomfort during balloon distension (2, 8, 9, 24, 29, 36, 37) has led
to the suggestion that these disorders are related to alterations in
visceral sensitivity (26-28). This new
pathophysiological concept has highlighted the need for standardized
reproducible methods of evaluating visceral sensitivity in humans. In
most studies, the evaluation of sensory perception has been based on subjective reports. Several approaches have been proposed for more
objective evaluation of visceral sensitivity. They include measurement
of intestinointestinal reflexes, recording of cortical potentials
evoked by visceral stimuli (1), and very recently, brain function
imaging (38). We developed a different approach based on the
counterirritation process, i.e., the inhibition of a pain by a
different pain. In a previous study in healthy volunteers (6), we
showed that gastric distensions induced stable reproducible inhibitions
of a somatic nociceptive flexion reflex, the RIII reflex. This reflex
is a polysynaptic spinal reflex elicited by electrical stimulation of a
sensory nerve and recorded from a flexor muscle in the ipsilateral
limb. The threshold and amplitude of the RIII reflex are closely
related to those of the concomitant cutaneous sensations evoked by
electrical stimulation (40). As inhibitions of this reflex by gastric
distensions were closely correlated to both the volume of distension
and the resulting visceral sensation, we proposed that the RIII reflex
technique could be used to evaluate visceral sensations and
somatovisceral interactions more objectively in humans. In this
connection, we recently showed that this method could be used to test
the pharmacological effects of fedotozine, a compound that acts on
visceral sensitivity (13).
Using a similar approach in the present study, we tested the effects of
rectal distensions on the RIII reflex. To differentiate between
segmental and heterosegmental effects, we compared the effects of
distensions on the RIII reflex recorded from the lower and
upper limbs, respectively. We also compared the effects of two
distension modes, rapid and slow ramp, which are supposed to stimulate
different rectal mechanoreceptors (25, 30, 35).
 |
METHODS |
After the protocol was approved by a local Ethics Committee, the
experiments were performed on 10 healthy volunteers (5 men and 5 women,
aged 20-40 yr) with no evidence of chronic or acute illness,
gastrointestinal symptoms, or altered bowel habits. Volunteers were
carefully briefed about the experimental procedure and gave informed
written consent to participate in the study.
Nociceptive Flexion Reflex (RIII Reflex)
The RIII reflex was elicited and recorded from both the lower and upper
limbs, according to previously described and validated techniques (6,
7, 40). Briefly, subjects were placed in a lateral decubitus position,
and the RIII reflex was elicited and recorded by an entirely
computerized system (Physio Labo system, Notocord, Igny, France). To
elicit the lower limb reflex, the sural nerve was electrically
stimulated at a frequency of 0.17 Hz (10 stimulations/min), via a pair
of surface electrodes placed 2 cm apart on the degreased skin overlying
the nerve within its retromalleolar path. To elicit the upper limb
reflex, the same stimuli were applied to cutaneous branches of the
ulnar nerve on the fourth and fifth fingers, by means of ring
electrodes. Each electrical stimulation consisted of a train of five
constant current pulses of 1 ms each. Electromyographic responses were recorded via surface electrodes fixed on the degreased skin overlying ipsilateral flexor muscles, namely the biceps femoris in the lower limb
and biceps brachialis in the upper limb. The RIII reflex response was
identified as a multiphasic signal appearing 90-180 ms after each
stimulation in the lower limb and 90-150 ms thereafter in the
upper limb. After amplification, each reflex response was digitized,
full-wave rectified, and integrated. This integrated surface was used
to quantify the RIII response. Before each rapid distension, the RIII
reflex threshold was determined by four successive sequences of
increasing and decreasing electrical stimulation of the sural nerve.
The intensity of nerve stimulation was then adjusted to 20% above the
threshold and kept constant throughout the control, distension, and
postdistension periods of each experimental sequence.
Rectal Distension
A polyvinyl oversize spherical bag with a maximal diameter of 10 cm and
infinite compliance up to a maximal volume of 600 ml was mounted on the
tip of a double-lumen polyvinyl tube (12 Fr), tightly folded,
lubricated, and inserted into the rectum. The distal attachment site
was 4 cm from the anal verge. The tube was secured in the correct
position with tape. Its proximal opening was linked to an electronic
barostat (INRA, Toulouse, France) that allowed controlled inflation and
deflation of the balloon with air and continuous monitoring and
recording of the volume and pressure inside the balloon. When in place,
the balloon was unfolded by slowly injecting air under controlled
pressure (<20 mmHg). The balloon was then completely deflated. After
a 15- to 20-min period of rest, the barostat was used to inflate the
balloon, either rapidly at 900 ml/min to a constant pressure plateau
(rapid distension) or continuously at a constant volume rate of 40 ml/min (ramp distension).
Perception of Rectal Distensions
Before the experiments, volunteers were informed of the visceral
sensations they might experience. They were ask to grade the sensation
elicited by the rectal distension from 0 to 6 on a verbal
questionnaire, as follows : 0, no perception; 1, initial perception; 2, sensation of gas; 3, sensation of stool; 4, urge to defecate or onset
of discomfort; 5, moderate pain; and 6, intense or unbearable pain. For
rapid distensions, subjects reported their sensation at the end of each
postdistension period. For slow-ramp distension, they reported their
sensation at the following fixed intervals: after every 100 ml of
distension up to 300 ml, and then after every 50 ml up to the pain
threshold (score 5). Whenever a sensation of intense or unbearable pain
(score 6) was experienced during any level of distension, the
distension was immediately suspended.
Experimental Design and Data Analysis
The 10 volunteers underwent experiments on 2 different days, separated
by an interval of 10-14 days. All experiments were performed after
a 12-h fast.
Day 1.
The respective effects of rapid phasic and continuous slow ramp were
tested on the RIII reflex recorded from the lower limb. The two types
of distension were performed in randomized order and separated by 1 h
of rest. Rapid distensions were performed at four levels (10, 20, 30, and 40 mmHg). Each level was applied once, and the order of application
was randomized. Each distension was maintained for 3 min, and
10-15 min elapsed between the application of each level of
distension to avoid sensitization phenomena. The RIII reflex responses
were measured during the 3 min before distension (control period),
during the 3-min distension period, and during the 3 min after
distension (postdistension period). For each level of distension, the
RIII responses were averaged at 1-min intervals and expressed as a
percentage of the mean control value. Slow-ramp rectal distension was
performed up to either the pain threshold or the maximum volume of the
balloon (600 ml). The RIII reflex responses were measured during the 4 min before distension (control period), during the continuous rectal
distension period, and during the 4 min after distension
(postdistension period). The sensations elicited by the distensions
were scored as described above.
Day 2.
The effects of four levels of rapid distensions (10-40 mmHg) were
tested on the RIII reflex recorded from the upper limb, using the same
experimental design as that used on
day
1. Slow-ramp distensions were not
performed, because of a lack of stability of the reflex recorded from
the upper limb (see below).
Statistical Analysis
Results were expressed as means ± SE. Statistical analysis of RIII
inhibition was performed by two-way ANOVA, with the Fishers post hoc
least-significant difference test. Relationships between two variables
were tested by the Kendall rank correlation (
). P < 0.05 was considered significant.
 |
RESULTS |
Effects of Rectal Distensions on RIII Reflex Recorded From Lower Limb
The mean threshold of sural nerve stimulation required to evoke the
RIII reflex from the lower limb was 9.4 ± 0.2 mA. Stimulation at
1.2 times the threshold level elicited a fairly stable RIII reflex
response during the predistension period (see control period in Fig.
1) and evoked a moderate painful sensation
of the pinprick type. Subjects reported that this sensation originated
from the level of the stimulating electrodes and was projected up to
the distal cutaneous receptive field of the sural nerve on the external side of the foot. The sensation fluctuated minimally and was well tolerated throughout the experiments (70-80 min).

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Fig. 1.
Individual example showing effects of rapid rectal distensions from 10 to 40 mmHg
(A-D)
on RIII reflex recorded from the lower limb. Arrows delimit 3-min
period of distension. Each bar represents a single reflex response,
expressed as a % of the mean value for the 3-min predistension control
period.
|
|
Rapid distensions.
The four levels of distension could be completed in all the subjects
except one who interrupted the 40-mmHg distension after 2 min. An
example of the effects of the four levels of rectal distension on the
RIII reflex is shown in Fig. 1, and the cumulative results observed in
the 10 volunteers are shown in Fig.
2. The 10-mmHg distension did
not significantly modify the RIII reflex during the 3 min of
distension. The 20- and 30-mmHg distensions induced a significant
increase in the reflex (i.e., facilitation) during the first minute of
distension (129 ± 5% and 159 ± 7% of mean control values,
respectively; P <0.001). The 40-mmHg
distension facilitated the RIII reflex during the first minute (127 ± 7% of mean control values; P < 0.001) and inhibited it during the second and third minute
(72 ± 8% and 66 ± 5% of mean control values, respectively; P < 0.001). The 10-, 20-, 30-, and 40-mmHg distensions elicited mean sensation scores of
1.2 ± 0.3, 2.9 ± 0.3, 3.6 ± 0.1, and 4.8 ± 0.1, respectively.

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Fig. 2.
Cumulative data showing effects of graded rapid rectal distensions
ranging from 10 to 40 mmHg
(A-D)
on RIII reflex recorded from the lower limb. For each distension level,
the mean RIII reflex response during each minute was expressed as a % of the mean value recorded during the 3-min predistension control
period. The 3-min distension period (solid bars) is indicated by
arrows. Data are means ± SE.
* P < 0.05, *** P < 0.001 vs. control
values.
|
|
Slow-ramp distension.
An example of the effect of slow-ramp distension on the RIII reflex
recorded from the lower limb is shown in Fig.
3A.
Cumulative results are given in Fig.
3B, which also shows the evolution of intrabag pressure during distension. Progressive inhibition of the
reflex was observed and reached its maximum (68 ± 9% inhibition of
mean control value) at the maximal level of distension (pressure, 38 ± 4 mmHg; volume, 398 ± 35 ml). As shown in Fig.
4, the inhibition of the RIII reflex
correlated with both the volume and the sensation scores.

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Fig. 3.
A: individual example showing effects
of slow-ramp rectal distension on RIII reflex recorded from the lower
limb. Each bar represents a single reflex response, expressed as a % of the mean value for the 4-min predistension control period. The
period of increasing distension is indicated by arrows.
B: cumulative data showing effects of
slow-ramp rectal distensions on RIII reflex recorded from the lower
limb ( ) and mean intrarectal pressure ( ) at each minute of
distension. The mean RIII reflex response during each minute was
expressed as a % of the mean value recorded during the 4-min
predistension control period. Data are means ± SE.
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Fig. 4.
A: relationship between volume of
rectal distension and sensation perceived, as assessed by verbal
questionnaire ( = 0.49; P < 0.0001). B: relationship
between volume of rectal distension and RIII reflex responses,
expressed as % of control values ( = 0.47;
P < 0.0001).
C: relationship between sensation
score and RIII reflex responses, expressed as % of control values ( = 0.49; P < 0.0001).
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|
Effects of Rectal Distensions on RIII Reflex Recorded From Upper
Limb
The mean threshold required to evoke the RIII reflex from the upper
limb was 8.5 ± 1.2 mA. In four subjects, the stimulation of the
cutaneous branches of the cubital nerve was not well tolerated, and/or the reflex responses were not stable enough during the control period. In the remaining six subjects, stimulation at 1.2 times
the threshold level elicited a RIII reflex response during the
predistension period that was judged stable enough. An example of the
effects of the four levels of rectal distension on the RIII reflex
recorded from the upper limb is shown in Fig. 5, and the cumulative results are indicated
in Fig. 6. Distension of 10 mmHg did not
significantly modify the RIII reflex, but the 20-, 30-, and 40-mmHg
distensions caused significant inhibition (72 ± 10%, 60 ± 6%,
and 54 ± 7% of mean control values, respectively; P < 0.01). Inhibitions
were maximal during the second and third minute of distension. For the
30- and 40-mmHg distensions, inhibitions outlasted the distension
period by 1 and 2 min, respectively. The 10-, 20-, 30-, and 40-mmHg
distensions elicited mean sensation scores of 0.7 ± 0.2, 2.8 ± 0.4, 4 ± 0.2, and 4.9 ± 0.1, respectively. Perception
scores correlated significantly with the levels of distension (
,
0.87; P < 0.001). In addition, a
significant correlation was observed between RIII reflex inhibition and
sensation scores (
, 0.55; P < 0.001).

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Fig. 5.
Individual example showing effects of rapid rectal distensions from 10 to 40 mmHg
(A-D)
on RIII reflex recorded from the upper limb. Each bar represents a
single reflex response, expressed as a % of the mean value for the
3-min predistension control period. The 3-min period of distension is
indicated by arrows.
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Fig. 6.
Cumulative data showing effects of graded rectal distensions ranging
from 10 to 40 mmHg
(A-D)
on RIII reflex recorded from the upper limb. For each distension level,
the mean RIII reflex response during each minute was expressed as % of
the mean value recorded during the 3-min predistension control period.
The 3-min distension period (solid bars) is indicated by arrows. Data
are means ± SE. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. control
values.
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|
 |
DISCUSSION |
The present results indicate that, in humans, rectal distensions induce
different effects on the RIII nociceptive flexion reflex, depending on
the site of recording (i.e., upper or lower limb) and the mode of
distension (i.e., rapid or slow ramp). The inhibitory effects were
probably due to the activation of pain modulation systems. Reflex
facilitation, which was only observed for the reflex recorded from the
lower limb, may well have been due to the convergence of somatic and
visceral inputs at the same levels of the spinal cord. The different
effects of rapid and slow-ramp distensions suggest that two
functionally distinct types of rectal mechanoreceptor were activated by
these different modes of distension.
Rapid rectal distensions induced inhibitions of the reflex recorded
from the upper limb that correlated with both the level of distension
and visceral sensation. These inhibitions were similar to those
observed for the RIII reflex recorded from the lower limb during
gastric distension (6). In both cases, a conditioning visceral
heterotopic stimulus was applied in an area far from the response
tested (i.e., the RIII reflex). These heterosegmental effects were
similar to those observed in animals. Thus, in the cat and rat, the
activities of nociceptive spinal dorsal horn neurons and somatic
nociceptive reflexes were indeed found to be strongly inhibited by
somatic or visceral heterotopic noxious conditioning stimuli (10, 15,
16, 21-23, 31, 34). Such inhibitory effects probably involved
systems that modulate the spinal transmission of nociceptive signals.
One such system, initially described in the rat (22, 23), is called
diffuse noxious inhibitory controls (DNIC). DNIC are triggered
exclusively by heterotopic nociceptive stimuli and are sustained by an
anatomic loop involving supraspinal structures located in the caudal
medulla (3-5). Using the RIII nociceptive flexion reflex as a test
response, it has been demonstrated that a supraspinally mediated system
analogous to DNIC and similarly organized also exists in humans (7, 14, 41, 42). Such a system probably constitutes one of the
neurophysiological bases for the counterirritation phenomenon (i.e.,
the inhibition of a pain by a different pain). However, in contrast to
heterotopic somatic stimuli, the present study and our previous one (6) indicate that inhibition of the RIII reflex is induced, not only by
nociceptive visceral stimuli, but also by nonpainful visceral stimuli.
Similar results have been observed in animals (10, 34). The differences
between the effects of heterotopic visceral stimuli and somatic stimuli
on the RIII reflex might be related to the specific organization
of the sensory receptors involved in visceral pain. Indeed, the
presence of specific nociceptors, well established in the skin, is
still controversial in the viscera, although high-threshold receptors
have been described in several regions of the gastrointestinal tract
(11, 12, 33). Alternatively, one cannot exclude the possibility that
other modulating systems, such as those entirely organized in the
spinal cord (17) or those mediated by vagal afferents, are also
involved in the inhibition of the RIII reflex.
More surprisingly, rapid rectal distensions had both facilitating and
inhibitory effects on the RIII reflex recorded from the lower limb.
Facilitation was observed during the initial period of low levels of
rectal distension and to a lesser extent, during the highest level of
distension. Because such facilitation was not observed when RIII reflex
was recorded from the upper limb, one plausible explanation is that it
was due to the convergence of rectal and RIII reflex afferents at the
same levels of the spinal cord. Other central mechanisms, such as a
general arousal induced preferentially by rapid distensions or the
activation of extrarectal pelvic receptors by abrupt visceral
displacements, are less likely, because they would have induced similar
effects for the reflexes recorded from the upper and lower limbs. The viscerosomatic convergence of nociceptive information is a process that
is often observed in animals during the recording of neuronal activity
in many regions of the central nervous system and is considered to be
the mechanism underlying referred pain (11, 12, 33). In particular, it
has been observed that some nociceptive lumbar neurons with a cutaneous
excitatory receptive field located on the lower limb, are activated
also by colorectal distension (32). The spinal projections of rectal
afferents are not completely understood in humans. Both sacral
(parasympathetic) afferents running in the pelvic nerve and lumbar
(sympathetic) afferents running in the splanchnic nerve have been
described (11, 12, 26, 33). The convergence of some of these afferents
with those of the RIII reflex, which is integrated in the lumbar and
sacral levels of the spinal cord, is therefore possible. Because
facilitations were observed only during the initial phase of the rapid
distensions, one can propose that convergence involved rectal afferent
pathways connected with functionally distinct mechanoreceptors
selectively activated by this type of distension (see below). In the
present study, it was interesting to observe that the highest level of rapid rectal distension induced brief facilitation of the reflex, followed by its inhibition. This biphasic effect suggests competition between the two processes (i.e., facilitation due to convergence and
inhibition due to inhibitory controls).
Unlike rapid distensions, slow-ramp rectal distensions only inhibited
RIII reflex recorded from the lower limb. These inhibitory effects,
which correlated with both the distension level and the visceral
sensation perceived, probably involved spinal and/or supraspinal mechanisms similar to those discussed above. In this respect, it would have been interesting to compare the effects of
slow-ramp distension on the upper and lower limb reflexes. However, the
effects of slow-ramp distensions were not tested on the upper limb
reflex, since electrical stimuli were less well tolerated and the RIII
reflex was much less stable in the upper limb.
Several lines of evidence suggest that different types of
mechanoreceptors are activated during rapid and slow-ramp rectal distension in humans: 1) in normal
volunteers, perception thresholds are higher for rapid than for
slow-ramp distension (30, 39), 2) in
patients with irritable bowel syndrome, sensory thresholds are reduced
for rapid distension but normal for slow-ramp distension (30), and
3) intrarectal lidocaine induced a
rise in perception thresholds during slow-ramp distension but not
during rapid distension, in both normal control subjects and patients
with irritable bowel syndrome (25). The results of electrophysiological
and anatomic studies in animals suggest that thoracolumbar afferents
have receptive fields located in the muscle layer, serosa, and
mesentery, whereas for sacral afferents the receptive fields are
mucosal (12, 18-20). In humans, it has been proposed that mucosal
mechanoreceptors are preferentially stimulated during slow rectal
distensions, whereas splanchnic afferents, whose receptive fields are
in the serosa and mesentery and project into the lumbar spinal cord, are preferentially activated during rapid distensions (25, 30). In
accordance with this hypothesis, it has been reported that patients
with sacral spinal cord lesions experienced residual perception during
rapid phasic rectal distensions but no sensation during slow-ramp
distensions (25). The opposite effects of rapid and slow-ramp
distensions on the RIII reflex recorded on the lower limb might be due
to the selective activation of these different populations of rectal
mechanoreceptors by the two modes of distension. However, one cannot
exclude the possibility that the facilitating effects observed here
were due to the greater synchronization of afferent activities induced
by rapid rather than slow-ramp distensions. One way of eliminating this
possibility would be to study the effects of both types of rectal
distension on the RIII reflex after intrarectal administration of
xylocaine to reduce the response of the superficial mucosal receptors.
In conclusion, the present results confirm the advantages of RIII
nociceptive reflex recording to evaluate visceral sensitivity in
humans. This approach might constitute an interesting tool for studying
both the changes in somatovisceral convergence and pain modulation
systems in various pathological states.
 |
ACKNOWLEDGEMENTS |
This study was supported by Institut National de la Santé et
de la Recherche Médicale (Clinical Research Network).
 |
FOOTNOTES |
Address for reprint requests: D. Bouhassira, INSERM U-161, 2, Rue
d'Alésia, 75014 Paris, France.
Received 10 October 1997; accepted in final form 16 April 1998.
 |
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