Download Involvement of the Caudal Medulla in Negative Feedback

Involvement of the Caudal Medulla in Negative Feedback Mechanisms
Triggered by Spatial Summation of Nociceptive Inputs
OLIVIER GALL, DIDIER BOUHASSIRA, DJAMEL CHITOUR, AND DANIEL LE BARS
Institut National de la Santé et de la Recherche Médicale U.161, 75014 Paris Cedex, France
spinal noci-responsive neurons has centered almost exclusively on their receptive fields. We recently have observed,
however, by applying noxious heat (487C) to their excitatory
receptive fields and also to adjacent, much larger, areas of
the body, that lumbar dorsal horn convergent neurons encode
variations in stimulus surface area with a nonmonotonic
transmission function (Bouhassira et al. 1995b). The function was first accelerating over a narrow range of areas
(above twice the area of individual receptive field). Further
increasing the stimulated surface resulted in a surface-dependant decrease in the responses of the neurons. Quantitatively, a reduction of Ç40% was observed when the responses evoked by stimulating a small area (4.8 cm2 , i.e.,
approximately twice the area of the excitatory receptive
fields of the recorded units) were compared with those
evoked by stimulating a larger area (18 cm2 , Ç10 times the
size of the excitatory receptive fields). Such effects were
not observed for neurons recorded in acutely spinalized animals. It was concluded that the recruitment of a large number
of spinal noci-responsive neurons by spatial summation of
nociceptive inputs triggers a negative feed-back loop modulating the activity of lumbar convergent neurons.
The aim of the present study was to determine at which
supraspinal level inhibitory controls triggered by spatial
summation are organized and hence to ascertain what relationships they might share with other descending controls
modulating spinal transmission of nociceptive signals in the
rat: namely the modulating systems organized within the
rostral ventromedial medulla (RVM) (Basbaum and Fields
1984; Fields and Basbaum 1989; Fields et al. 1991), those
involving more rostral brain stem structures, e.g., the periaqueductal gray (PAG) (see refs. in Besson and Chaouch
1987; Fields and Basbaum 1989; Willis 1988; Willis and
Coggeshall 1991; Zieglgänsberger 1986) and diffuse noxious inhibitory controls (DNIC). The later have been shown
to depend solely on structures in the caudal medulla (Bouhassira et al. 1990, 1992a,b, 1993, 1995a).
METHODS
INTRODUCTION
Surgical preparation
By comparison with experimental situations where tiny
areas of stimulation are used often, painful foci encountered
in clinical practice are not punctuate: they presumably involve a large number of excitatory receptive fields of peripheral fibers and central neurons. Thus spatial summation may
be an important aspect of processing of nociceptive information as it is also for other cutaneous senses (Hardy et al.
1952; Marks et al. 1973). The study of the properties of
304
Experiments were performed on male Sprague-Dawley rats
weighing 200–250 g. The animals were housed with ad libitum
access to food and water in a room illuminated from 06.00 to 18.00
h. Anesthesia was induced by 2.5% halothane in a N2O:O2 mixture
(2:1). Tracheal and jugular cannulae were inserted. The animal
then was paralyzed by intravenous injection of gallamine triethiodide (Flaxedil) and ventilated artificially. The rate (50–55 strokes/
min) and volume of ventilation were adjusted to maintain a normal
0022-3077/98 $5.00 Copyright q 1998 The American Physiological Society
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Gall, Olivier, Didier Bouhassira, Djamel Chitour, and Daniel
Le Bars. Involvement of the caudal medulla in negative feedback
mechanisms triggered by spatial summation of nociceptive inputs.
J. Neurophysiol. 79: 304–311, 1998. In the rat, applying noxious
heat stimuli to the excitatory receptive fields and simultaneously
to adjacent, much larger, areas of the body results in a surfacerelated reduction in the responses of lumbar dorsal horn convergent
neurons. These inhibitory effects induced by spatial summation of
nociceptive inputs have been shown to involve a supraspinally
mediated negative feedback loop. The aim of the present study
was to determine the anatomic level of integration of these controls
and hence to ascertain what relationships they might share with
other descending controls modulating the transmission of nociceptive signals. The responses of lumbar convergent neurons to noxious stimulation (15-s immersion in a 487C water bath) applied to
increasing areas of the ipsilateral hindlimb were examined in several anesthetized preparations: sham-operated rats, rats with acute
transections performed at various levels of the brain stem, and
spinal rats. The effects of heterotopic noxious heat stimulation (tail
immersion in a 527C water bath) on the C-fiber responses of these
neurons also were analyzed. The electrophysiological properties
of dorsal horn convergent neurons, including their responses to
increasing stimulus surface areas, were not different in sham-operated animals and in animals the brain stems of which had been
transected completely rostral to a plane 02.8 mm remote from
interaural line (200 mm caudal to the caudal end of the rostral
ventromedial medulla). In these animals, increasing the stimulated
area size from 4.8 to 18 cm2 resulted in a 35–45% reduction in
the responses. In contrast, relative to responses elicited by 4.8 cm2
stimuli, responses to 18 cm2 were unchanged or even increased in
animals with transections at more caudal level and in spinal animals. Inhibitions of the C-fiber responses elicited by heterotopic
noxious heat stimulation were in the 70–80% range during conditioning in sham-operated animals and in animals with rostral brain
stem transections. Such effects were reduced significantly (residual
inhibitions in the 10–20% range) in animals with transections
ú500 mm caudal to the caudal end of the rostral ventromedial
medulla and in spinal animals. It is concluded that the caudal
medulla constitutes a key region for the expression of negative
feed-back mechanisms triggered by both spatial summation of noxious inputs and heterotopic noxious inputs.
SPATIAL SUMMATION AND NOCICEPTION
Electrophysiological recordings
Recordings were commenced 30–45 min after the end of the
preparatory surgery. Single neurons were recorded extracellularly
in the right or left lumbar dorsal horns with the animals now
anesthetized with 0.5% halothane in 33% O2 and 67% N2O.
Recordings were made with glass micropipettes (10–15 MV )
filled with 5% NaCl and pontamine sky blue. Neurons were classified as convergent on the basis of their responses to both innocuous
and noxious mechanical stimulation of their receptive fields. Light
mechanical stimuli produced with a blunt probe and noxious pinch
were used to characterize each recorded unit and to delineate its
excitatory receptive field, which was taken as the area of skin from
which the cell could be activated by such stimuli. The receptive
field area of the cell was reexamined before each thermal stimulus
was applied (see further text). Recording sites in the lumbar dorsal
horn were marked using dye electrophoresis from the micropipettes
at the end of the experiments.
Thermal stimulation procedure
To investigate the effects of spatial summation from nociceptive
afferents, we tested for each neuron the responses elicited by noxious stimuli applied to two different areas of the ipsilateral hindpaw, namely, area 1, all five digits (4.8 cm2 ), and area 2, the paw
°20 mm below the knee (18 cm2 ). The noxious stimuli involved
immersing the area for 15 s in a 487C water bath. These thermal
stimuli were applied in random order with a 10-min interval. In a
previous study (Bouhassira et al. 1995b), we showed that such a
procedure allowed the recording of reproducible responses without
significant sensitization or desensitization phenomena. To reduce
further the possibility of sensitization or desensitization resulting
from repetitive noxious stimulation (Cervero et al. 1988; Cook et
al. 1987; Ferrington et al. 1987; Kenshalo et al. 1979, 1982), no
more than two neurons, one in each side of the cord, were recorded
in each animal. Only cells that presented no serious changes in
spike amplitude or wave form during the complete experimental
procedure were considered.
None of the stimuli significantly modified heart rate (any
changes were of õ5 beats/min). Blood pressure was not monitored
in all the animals. Results concerning cardiovascular changes ob-
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served in a similar series of brain stem transected animals are
reported elsewhere (Bouhassira et al. 1995a).
Electrical stimulation procedure
After the thermal stimulation sequence, the effects of applying
electrical stimuli to the center of the receptive field of the recorded
unit were investigated. All the neurons studied gave responses with
latencies corresponding to A- and C-fiber inputs.
To investigate the effects of the transections on DNIC, we tested,
on the same neurons, the effects of heterotopic noxious stimuli
on the C-fiber responses evoked by electrical stimulation of their
receptive fields. A sequence of 105 electrical stimuli (percutaneous
single square-wave pulses, 2-ms duration, at an intensity of twice
the threshold for C-fiber evoked responses) was applied once every
1.5 s. A multichannel analyzer (Tracor TN 1710) was used online to build poststimulus histograms (PSH). The first 50 responses
were not taken into consideration because they showed either habituation or, more usually, ‘‘wind-up’’ phenomena. The PSH built
from the 50th to the 65th responses was used as a control for the
sequence. The conditioning stimulus (immersion of 17.3 cm2 of
the tail in a 527C water bath) was applied between the 65th and
90th electrical stimuli, and a PSH built from the 75th to 90th
responses was used to assess the effects of the conditioning stimulus. A PSH built from the 91st to the 105th responses allowed
posteffects to be observed during the first 22 s after the removal
of the conditioning stimulus. The PSHs were analyzed with responses due to A- and C-fiber inputs being distinguished by their
latencies. Inhibitions were expressed as percentage decreases in
the number of spikes for both the A- and C-fiber evoked responses
with reference to the control PSH. Only the C-fiber component is
considered in the present report.
Histological determination of the levels of transection
At the end of the experiments, animals were anesthetized deeply
(3.5% halothane) and perfused through the heart with saline followed by a 10% formalin solution to enable histological sections
to be prepared. The level of transection was considered as the most
rostral areas of the brain stem spared by the transection. All the
sections were examined by the same observer, who was unaware
of the electrophysiological results, with reference to the stereotaxic
atlas of the rat brain by Paxinos and Watson (1986).
For analysis purposes, the levels of transections were pooled
into four groups (I–IV ) as represented in Fig. 1. Animals were
assigned to group I when the most rostral brain stem plane spared
by the transection was located between 01 mm to the interaural
line (the caudal end of locus coeruleus dorsally to the trapezoid
body ventrally) and 01.8 mm (the rostral third of the medial
vestibular nucleus dorsally to the rostral third of the lateral paragigantocellular nucleus ventrally). In group II, the levels of transections were located between 02 mm to the interaural line (the
medial third of the medial vestibular nucleus dorsally to the lateral
paragigantocellular nucleus ventrally) and 02.8 mm (the caudal
third of the medial vestibular nucleus dorsally to the inferior olive
ventrally). In group III, transections were located between 03.3
mm to the interaural line (the caudal end of the medial vestibular
nucleus dorsally to the medial inferior olive ventrally) and 04 mm
(the solitary nucleus dorsally to the caudal third of the inferior
olive ventrally). In group IV, the transections extended between
04.2 mm to the interaural line (the hypoglossal nucleus dorsally
to the lateral reticular nucleus ventrally) and 05 mm (the caudal
end of the hypoglossal nucleus dorsally to the lateral reticular
nucleus ventrally).
Data are presented as means { SE. Background activity was
analyzed during the 10 s preceding each stimulation period. Noxious-heat evoked responses were calculated as the total number of
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acid-base equilibrium (end-tidal CO2 : 3.5–4.5%) as assessed with
a capnometer (Capnomac II, Datex Instruments, Helsinki, Finland), which also measured O2 , N2O and halothane levels throughout the experiment. Heart rate was monitored continuously and core
temperature maintained at 37 { 0.57C by means of a homeothermic
blanket system.
The animals were mounted in a stereotaxic frame. In 33 animals,
the brain stem was transected acutely, at different levels between
01 and 05 mm from interaural coronal plane, as described previously (Bouhassira et al. 1995a). Briefly, after fenestration of the
occipital bone and aspiration of the cerebellum, a surgical knife
was inserted medially through the brain stem until contact with
the skull was felt at which point the knife was moved gently from
side to side. To ensure complete transection, 2–3 mm of brain
stem substance rostral to the cut were removed by aspiration. Hemostasis was achieved by thermocoagulation and the application
of gelfoam. Twelve sham-operated control animals underwent the
same procedure (including aspiration of the cerebellum) except for
brain stem transection. In another 12 animals, the brain stem was
not transected and the spinal cord was sectioned at the level of
the rostral border of the second cervical vertebrae. After these
procedures, a laminectomy was made to enable electrophysiological recordings to be made from the lumbar dorsal horn (segments
L3 –L4 ).
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306
O. GALL, D. BOUHASSIRA, D. CHITOUR, AND D. LE BARS
levels of firing before the first and the second test were not
significantly different [F(1,138) Å 1.37, n.s.].
Spatial summation of noxious heat
action potentials during the 15 s of the heat stimulus and corrected
for background activity. Analyses of variance and post hoc Fisher’s
least significant difference tests were used for statistical purposes;
P values õ 0.05 were considered to be significant.
RESULTS
Recordings were made from 70 convergent neurons: 12
in sham-operated control animals, 8 in group I, 12 in group
II, 14 in group III, and 12 in group IV brain stem-transected
animals, and 12 in the spinal (C2 ) animals (see Fig. 1 and
methods for the group assignment rules). In all the preparations, convergent neurons were located similarly in the deep
layers of the dorsal horn as evidenced by the dye electrophoresed from the micropipettes at the end of the experiments.
General characteristics of the cells
The excitatory receptive fields of the recorded units were
located distally on the ipsilateral hindpaw and covered one
to five digits. The mean area of the excitatory receptive fields
were not significantly different between sham-operated, spinal, and any group of transected animals [F(5,64) Å 1.01,
n.s.]. These data are reported in Table 1. Subsequent receptive field mapping before the second noxious heat stimulation revealed only inconsistent and nonsignificant changes
[F(1,138) Å 0.86, n.s.].
As summarized in Table 1, spontaneous activity was similar for neurons recorded in sham-operated and in group I
and II transected animals but was significantly higher for
neurons recorded in the most caudally transected animals
(groups III and IV ) and the spinal animals [F(5,64) Å 4.14,
P Å 0.025]. In addition, in all the preparations, spontaneous
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Inhibition of the C-fiber response elicited by heterotopic
noxious heat stimulation
The thresholds for the C-fiber evoked responses elicited
by transcutaneous electrical stimulation (2-ms duration)
were not influenced by the level of transection; mean values
of 2.1 { 0.49, 2.8 { 0.75, 2.5 { 0.38, 3.0 { 0.34, 2.7 {
0.45, and 2.7 { 0.23 mA were obtained for sham-operated,
group I, group II, group III, group IV, and spinal animals,
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FIG . 1. Drawing of a sagittal section of the brain stem adapted from
Paxinos and Watson (1986), showing the rostral and caudal limits (shaded
areas) of the transections in the 4 groups of transected animals. Numbers
on the scale show the anteroposterior distance from the coronal plane passing through the interaural line.
Individual examples of the responses elicited by the small
and large thermal stimuli in the different preparations, are presented in Fig. 2. In sham-operated and in groups I and II transected animals, the responses elicited by the 18 cm2 stimulus
were clearly smaller than those elicited by 4.8 cm2 . By contrast,
in groups III and IV and in spinal animals, the responses elicited
by the two stimulus areas did not appear to be different.
Cumulative results concerning noxious-heat evoked-responses (expressed as mean firing rate during the 15 s) in the
different experimental groups are reported in Table 1. The mean
discharge rate elicited by immersion of the digits (4.8 cm2 ) was
similar in all preparations, except for neurons recorded in group
IV, which displayed a surprisingly low discharge rate.
In sham-operated and in group I and II transected animals,
increasing stimulus size from 4.8 to 18 cm2 resulted in a
35–40% reduction in the responses. In contrast, in groups
III and IV and in the spinal animals, the responses elicited
by the 18 cm2 stimuli were not significantly different from
those evoked by the 4.8 cm2 stimuli. Such differences were
not dependant on the order of application of the stimuli.
Global comparison of thermal stimulation sequences e.g.,
4.8–18 cm2 or 18–4.8 cm2 revealed no significant differences in the recorded responses [F(1,136) Å 1.15, n.s.].
Furthermore, as stressed earlier, indicators of sensitization
such as the background discharge rate of the recorded units
or the sizes of their excitatory receptive fields were not modified significantly during the course of the experiments.
The influence of the level of brain stem transection on the
pattern of responses to graded thermal stimuli is summarized
in Fig. 3, where the results are expressed as percentages
(100 1 response to 18 cm2 /response to 4.8 cm2 ). In shamoperated animals, the mean discharge rate elicited by immersion of the entire paw (18 cm2 ) was 65 { 9% of the mean
discharge rate elicited by immersion of the digits (4.8 cm2 ).
Similar effects were observed in group I and group II transected animals (responses elicited by the 18 cm2 stimuli were
58 { 12% and 54 { 8% of the responses evoked by the 4.8
cm2 stimuli, respectively). In contrast, no decrease, or even
an increase in the responses elicited by the larger stimuli, was
observed for neurons recorded in group III and IV transected
animals and in the spinal animals (the mean values being
114 { 23% in group III transections, 127 { 13% in group
IV transections, and 120 { 14% in the spinal animals). Analysis of variance revealed significant intergroup differences between sham-operated, group I, group II, group III, group IV,
and spinal animals [F(5,64) Å 4.82, P Å 0.008].
SPATIAL SUMMATION AND NOCICEPTION
TABLE
1.
307
Summary of the main electrophysiological data obtained in the experimental groups
Thermal Responses
n
Sham
Group
Group
Group
Group
Spinal
I
II
III
IV
12
8
12
14
12
12
Receptive Field Area,
cm2
1.7
1.7
1.6
1.9
2.0
2.0
{
{
{
{
{
{
Background Activity,
ap/s
4.8 cm2 stimulus,
ap/s
{
{
{
{
{
{
83.9 { 11.8
95.7 { 12.0
97.5 { 20.6
85.8 { 16.2
49.3 { 10.5†
86.2 { 14.0
0.2
0.3
0.2
0.2
0.4
0.3
2.9
2.2
2.7
15.9
18.9
11.5
0.8
0.9
0.8
2.2*
2.6*
2.0*
18 cm2 stimulus,
ap/s
58.3
58.7
58.1
79.7
59.9
94.4
{
{
{
{
{
{
12.0
13.3
18.4
14.5
12.1
13.8
All data are means { SE. Spontaneous and evoked activity are expressed as action potentials/second (ap/s). * Comparison versus sham-operated, group
I or group II: P õ 0.05. † Comparison versus group II: P õ 0.05.
DISCUSSION
The spatial summation of nociceptive inputs can trigger
a supraspinally mediated feed-back inhibition of activity in
FIG .
2. Individual examples of the responses of convergent neurons
recorded in the different preparations (from bottom: sham, groups I, II, III,
and IV, transected, and spinal animals). Each histogram (binwidth Å 0.5
s) represents the responses evoked by the immersion of 4.8 cm2 (left) or
18 cm2 (right) of the ipsilateral hindpaw. Timing of the stimulus (15-s
duration) is indicated by the horizontal bar below each histogram. In the
sham-operated and the group I and II transected animals, the responses
elicited by the 18 cm2 stimulus were smaller than that evoked by the 4.8
cm2 stimulus. In contrast, in group III and IV transected and spinal animals,
the responses elicited by the 2 stimulation areas were not different; note
also that spontaneous activity and poststimulus discharges were higher in
these preparations.
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FIG . 3. Bar charts representing the noxious heat (487C, 15 s) evoked
responses to stimulation of the whole paw (18 cm2 ) as percentages of the
responses to stimulation of the digits alone (4.8 cm2 ) in the different groups
of animals. In sham-operated animals, the mean discharge rate elicited by
immersion of the whole paw was 65% of the mean discharge rate elicited
by the immersion of the digits. A similar effect was observed in group I
and group II transected animals. In contrast, convergent neurons recorded
in group III and group IV transected animals and in spinal animals responded to increasing the stimulus area with no reduction or even an increase in the response. Significant intergroup differences in these percentage
values existed between neurons recorded in sham-operated, group I and
group II animals and those recorded in group III, group IV, and spinal
animals (**P õ 0.01, ***P õ 0.001 vs. sham operated).
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respectively [F(5,64) Å 1.35; n.s.]. Increasing the level of
stimulation to twice threshold resulted in mean responses of
17.4 { 2.5, 11.7 { 1.7, 13.8 { 2.7, 15.0 { 2.2, 17.9 { 4.2,
and 14.6 { 3.3 C-fiber latency action potentials per stimulus
for the respective groups [F(5,64) Å 0.60; n.s.].
The percentage inhibition of the C-fiber–evoked responses induced by the noxious heterotopic stimulus, i.e.,
immersion of tail in a 527C water bath, are presented in Fig.
4. In sham-operated animals and in group I and II transected
animals, inhibition of the C-fiber–evoked responses elicited
by application of heterotopic noxious heat stimuli were in
the 70–80% range during conditioning. Poststimulus effects—in the 30–35% range—were observed during the
subsequent 22 s in these animals. In contrast, significantly
smaller inhibitions—in the 10–20% range—were observed
in group III, group IV, and spinal animals [F(5,64) Å 8.15,
P õ 0.001]. The postconditioning effects also were reduced
significantly (5–10% range) in these animals.
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O. GALL, D. BOUHASSIRA, D. CHITOUR, AND D. LE BARS
dorsal horn convergent neurons (Bouhassira et al. 1995b).
We now have confirmed these results and provided additional information regarding the anatomic localization of the
neuronal circuits involved in these processes. The relationships between these controls and previously described tonic
and phasic descending inhibitory controls will be discussed.
The general electrophysiological properties of convergent
neurons and the relationship between their responses and the
stimulus area were very similar in the sham-operated animals
and those with rostral brain stem transections. In contrast,
the spontaneous activity of the neurons increased and the
inhibitions triggered by spatial summation of nociceptive
afferent decreased, in animals transected more caudally than
a plane 500 mm caudal to RVM (i.e., in groups III and IV )
and in the spinal animals.
It seems very unlikely that cardiovascular changes induced by the transection could explain the present results.
In a previous study using a similar methodology for brain
stem transections (Bouhassira et al. 1995a), we showed that
decreases in resting arterial blood pressure and heart rate
appeared only in animals with brain stem transections at the
most caudal level, corresponding to group IV and spinal
animals. These results were in keeping with classical data,
which indicate that only destruction of the whole rostrocaudal extent of the rostral ventrolateral medulla induces significant reductions in resting blood pressure and heart rate
(see references in Chalmers and Pilowsky 1991; Dampney
1994; Spyer 1994).
The inhibitory phenomena triggered by spatial summation
of nociceptive inputs are very different from segmental inhibitory controls. Indeed, the latter have been observed in
both intact and spinal animals (see references in Besson
and Chaouch 1987; Willis and Coggeshall 1991) and are
activated preferentially by nonnoxious stimuli applied to the
inhibitory receptive field that often surrounds the excitatory
receptive field of convergent neurons (Besson and Chaouch
1975; Handwerker et al. 1975; Hillman and Wall 1969; Price
et al. 1978; Wagman and Price 1969). For all the neurons
in the present study, the smaller stimulus area (4.8 cm2 )
completely covered their excitatory receptive fields. In fact,
for the majority of the recorded units, this area was 1.5–2
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FIG . 4. Bar charts illustrating the percentage inhibitions of C-fiber–
evoked responses during conditioning stimulation (immersion of the tail
in a 527C water bath). In sham-operated animals and in group I or group
II animals, inhibition of the C-fiber–evoked responses induced by the heterotopic noxious heat stimulus were in the 70–80% range. By contrast,
significantly smaller inhibitions (in the 10–20% range) were observed in
group III, group IV, and spinal animals (***P õ 0.001 vs. sham operated).
times larger than that of their excitatory receptive fields. In
a previous study (Bouhassira et al. 1995b), we showed that
such an area was not large enough to trigger significant
inhibition due to spatial summation. These results do not
exclude the possibility that segmental influences, whether
excitatory or inhibitory, are the main source of modulation
of the activity of convergent neurons when nociceptive inputs are restricted to small areas.
Propriospinal inhibitory mechanisms acting on lumbar
dorsal horn convergent neurons also have been described in
various species including rats (Cadden et al. 1983; Zhang
et al. 1996), cats (Sandkühler et al. 1993), and monkeys
(Gerhart et al. 1981; Hobbs et al. 1992). Foreman and his
colleagues demonstrated that somatic or visceral noxious
inputs can trigger potent inhibitions of convergent neurons
activities via a relay in the upper cervical cord (Hobbs et
al. 1992; Zhang et al. 1996). Even though low spinal transections were not performed in the present study, the level of
residual inhibitions seen in group III, group IV, and spinal
animals are very low. Hence our results do not support an
important participation of the upper cervical cord in the negative feedback mechanisms triggered by spatial summation.
One cannot exclude, however, that both mechanisms may
act additively or synergisticaly to modulate the processing
of nociceptive information by convergent neurons in intact
animals.
The major finding of the present study is that phasic descending inhibitory controls triggered by spatial summation
of nociceptive inputs are integrated in the most caudal part
of the medulla. Thus these controls are topographically independent of the multiple modulatory controls originating from
more rostral brain stem structures (see references in Besson
and Chaouch 1987; Fields and Basbaum 1989; Willis 1988;
Willis and Coggeshall 1991). Notably, the PAG-RVM system is not directly involved in this negative feedback loop.
The participation of the RVM in an inhibitory feedback loop
initially had been proposed (Basbaum and Fields 1984;
Fields and Basbaum 1989). However, on the basis of the
electrophysiological properties of RVM neurons, it subsequently was suggested that both facilitatory and inhibitory
controls acting on the spinal transmission of nociceptive
signals originate in this region (Fields 1992; Fields et al.
1991). The RVM also might be involved in the integration
of adaptive cardiovascular responses induced by noxious
stimuli (see references in Lovick 1991; Thurston and Randich 1992) and/or in the modulation of the motor facet of
nociceptive reflexes (Lundberg 1964, 1982; Morgan et al.
1994, 1995).
DNIC also were reduced significantly in animals transected more caudally than a plane 500 mm caudal to RVM
(i.e., in groups III and IV ) and in the spinal animals. This
result confirms a previous study (Bouhassira et al. 1995a).
Thus the level of integration of descending inhibitory controls triggered by spatial summation and DNIC appeared to
be identical. Indeed, in all six types of preparation, a strong
correlation existed between inhibitions triggered by spatial
summation and inhibitions triggered by heterotopic noxious
stimuli. This result supports the view that spatial summation,
whether obtained by increasing the surface of a single stimulated area or by applying an additional stimulus to a remote
part of the body, can trigger negative feedback loops acting
SPATIAL SUMMATION AND NOCICEPTION
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are not punctuate and always involve a large number of
excitatory receptive fields of peripheral fibers and central
neurons. However the study of noci-responsive spinal neurons has centered almost exclusively on their receptive fields.
The investigation of the behavior of such neurons in situations closer to those for clinical pain has allowed us to characterize a nonmonotonic transmission function. Increasing
the injured area results in two functionally opposite effects:
an increase in the number of neurons activated and a decrease in the responses of the individual neurons. The consequences of such opposite effects on the resulting output of
the spinal cord and finally on the elaboration of pain sensation may be questioned. This point already has been the
subject of study of several investigators. When tested with
radiant heat, over areas extending °200 cm2 , it has been
reported that little or no spatial summation exist for heat
pain threshold (Greene and Hardy 1958; Hardy et al. 1940;
Marks and Stevens 1973; Stevens and Marks 1971; Stevens
et al. 1974). In contrast, studies conducted with contact
stimulators invariably established a significant decrease in
pain threshold when stimulus area was increased (Defrin
and Urca 1996; Kojo and Pertovaara 1987; Machet-Pietropaoli and Chery-Croze 1979). The perceived pain intensity
to suprathreshold contact heat stimulation also was found
positively correlated with the stimulus area in the 0–3 cm2
range (Douglass et al. 1992; Price et al. 1989).
One can speculate that one source of such discrepancies
lies in variable involvement of the descending inhibitory
controls triggered by spatial summation. Indeed, as stressed
above, the stimulation of small areas might not be sufficient
to trigger significant inhibition due to spatial summation,
hence leading to an increase of the net input received by
supraspinal target neurons when the stimulated area increases over a narrow range. A further increase of the area
could slow down such encoding function by triggering descending inhibitions, as shown here. In this respect, it would
be interesting to investigate psychophysically the effects of
very large noxious stimulations able to recruit a population
of noci-responsive neurons extending from L4 to S1 dermatomes for example, thus comparable in size with our present
data.
Alternatively, it is possible that, as the number of activated
spinal neurons increases, a decrease in individual responses
of these neurons will have little influence on the global input
received by supraspinal target neurons involved in the elaboration of pain sensation. This proposal might be investigated
during recordings of target supraspinal neurons. Villanueva
et al. (1989) examined the effects of spatial summation on
SRD neurons and observed that such neurons encode the
stimulus area with an accelerating function within a restricted range ( °6 cm2 ), whereas further increase in stimulus area resulted in a decrease of the responses. Interestingly,
in animals with lesion of the dorsolateral funiculus, the responses of SRD neurons to stimulation of increasing areas
became positively accelerating over the range studied (0.9–
25 cm2 ) (Villanueva et al. 1996). Obviously, further studies
are needed to examine the encoding of the tridimensional
characteristics of noxious events, namely intensity duration
and area, in other supraspinal structures involved in pain
processing.
In conclusion, the present data emphasize the role of the
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on dorsal horn convergent neurons. In both cases, the inhibitory controls are subserved by neuronal pathways organized
in the most caudal part of the medulla.
Such a role of the caudal medulla in descending modulatory systems acting on dorsal horn noci-responsive neurons
has been suggested previously (Aicher and Randich 1990;
Almeida et al. 1996; Gebhart and Ossipov 1986; Gebhart
and Randich 1990; Janss and Gebhart 1988a,b; Morgan et
al. 1989; Ren et al. 1990). Thus in addition to segmental,
propriospinal, and supraspinal descending systems originating from other brain stem structures, the caudal medulla
represents another specific level for the modulation of nociceptive signals. Such a role is further supported by recent
electrophysiological and anatomic data that indicate that the
subnucleus reticularis dorsalis (SRD) is involved in both the
transmission and the modulation of nociceptive information
(Villanueva et al. 1996). Other caudal medullary structures
such as the nucleus of the solitary tracts and the lateral
reticular nucleus, also might be involved in the modulation
of the spinal transmission of nociceptive signals (Aicher
and Randich 1990; Gebhart and Ossipov 1986; Gebhart and
Randich 1990; Janss and Gebhart 1988a; Janss et al. 1987;
Morgan et al. 1989; Ren et al. 1990).
Another finding in this study concerns tonic descending
inhibition. The existence of tonic descending inhibitory controls has been suggested on the basis of both behavioral and
electrophysiological experiments (see references in Besson
and Chaouch 1987; Willis 1988). It was observed that the
excitability of lumbar convergent neurons was higher (as
evidenced by increased spontaneous activity and responses
to noxious stimuli and/or by increased receptive field sizes)
after reversible cooling (‘‘cold block’’) of the cervical spinal
cord (Besson and Chaouch 1975; Brown 1971; Cervero and
Plenderleith 1985; Handwerker et al. 1975; Laird and Cervero 1990; Wall 1967). The descending pathways involved
in tonic descending inhibition probably are located in the
dorsolateral funiculus (Jones and Gebhart 1987; Pubols et
al. 1991; Sandkühler et al. 1987; Villanueva et al. 1986).
Duggan and his colleagues concluded on the basis of a series
of studies in the cat that the main supraspinal source of tonic
descending inhibition was in an area ventral to the facial
nucleus (Foong and Duggan 1986; Hall et al. 1982; Morton
et al. 1983, 1984). The supraspinal origin of tonic descending inhibition in the rat is not known. The present results
suggest that some tonic descending inhibition was removed
in the most caudally transected animals (group III, group
IV, and spinal animals) because the spontaneous activity of
convergent neurons was significantly higher in these animals. However, under our experimental conditions, the mean
size of excitatory receptive fields, the threshold and magnitude of C-fiber evoked responses, the responses evoked by
the stimulation of the 4.8 cm2 area (the mean number of
spikes and the pattern of the responses) were not significantly different between sham-operated animals and those
with brain stem or spinal transections. Such a differential
effect on evoked and nonevoked activities has been observed
previously (Janss and Gebhart 1988b; Jones and Gebhart
1987; Villanueva et al. 1986).
The present data also raise some questions concerning the
role of spatial summation in the processing of nociceptive
information. Painful stimuli encountered in clinical practice
309
310
O. GALL, D. BOUHASSIRA, D. CHITOUR, AND D. LE BARS
caudal medulla in descending modulatory systems acting on
dorsal horn noci-responsive neurons. The phasic controls
originating from this area seems to be dependant on the
spatial characteristics of nociceptive stimuli. Such an interpretation does not exclude the possibility of interactions with
other spinally or supraspinally organized modulatory systems in the processing of nociceptive information.
The authors thank Dr. S. W. Cadden for advice in the preparation of the
manuscript and J. Carroué for the histology.
This work was supported by l’Institut National de la Santé et de la
Recherche Médicale, la Direction de la Recherche et de la Technologie,
and l’Institut UPSA de la Douleur.
Address reprint requests to: O. Gall.
Received 7 May 1997; accepted in final form 29 August 1997.
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