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JOURNALOFNEUROPHYSIOLOGY
Vol. 63, No. 3, March 1990. Printed in U.S.A.
Ascending Pathways in the Spinal Cord Involved in the Activation
of Subnucleus Reticularis Dorsalis Neurons in the Medulla of the Rat
ZHU BING, LUIS VILLANUEVA, AND DANIEL LE BARS
Institut National de la Sante’ et de la Recherche Mbdicale, Unite’ de Recherches
de Physiopharmacologie du SystPme Nerveux, 75014 Paris, France
SUMMARY AND CONCLUSIONS
1. Recordings were made from neurons in the left medullary
subnucleus reticularis dorsalis (SRD) of anesthetized rats. Two
populations of neurons were recorded: neurons with total noci-
ceptive convergence (TNC), which gave responses to A& and
C-fiber activation from the entire body after percutaneous elec-
trical stimulation, and neurons with partial nociceptive conver-
gence (PNC), which responded to identical stimuli with an A&
peak regardless of which part of the body was stimulated and with
a C-fiber peak of activation from some, mainly contralateral,
parts of the body.
2. The effects of various, acute, transverse sections of the cer-
vical (C,-C,) spinal cord on the A& and C-fiber-evoked re-
sponses were investigated by building poststimulus histograms
(PSHs) after 50 trials of supramaximal percutaneous electrical
stimulation of the extremity of either hindpaw (2-ms duration; 3
times threshold for C-fiber responses), before and 30-40 min after
making the spinal lesion.
3. In the case of TNC neurons, hemisections of the left cervical
cord blocked the responses elicited from the right hindpaw and
slightly, but not significantly, diminished those evoked from the
left hindpaw. Conversely, hemisections of the right cervical cord
abolished TNC responses elicited from the left hindpaw with-
out significantly affecting the responses elicited from the right
hindpaw.
4. Lesioning the dorsal columns or the left dorsolateral funicu-
lus was found not to affect the TNC neuronal responses elicited
from either hindpaw. By contrast, lesioning the left lateral funicu-
lus or the most lateral part of the ventrolateral funiculus, respec-
tively, reduced and blocked the responses elicited from the right
hindpaw without affecting those evoked from the left hindpaw.
5. After lesions that included the most lateral parts of the left
ventral funiculus, PNC neuronal responses elicited from the right
hindpaw were also abolished, whereas those elicited from the left
hindpaw remained unchanged.
6. We conclude that the signals responsible for the activation
of SRD neurons travel principally in the lateral parts of the ven-
trolateral quadrant, a region that classically has been implicated
in the transmission of noxious information. Both a crossed and a
double-crossed pathway are involved in this process. The post-
synaptic fibers of the dorsal columns and the spinocervical and
spinomesencephalic tracts do not appear to convey signals that
activate SRD neurons.
7. The findings also suggest that lamina I nociceptive specific
neurons, the axons of which travel within the dorsolateral funicu-
lus, do not contribute very much to the activation of SRD
neurons.
INTRODUCTION
Since the earlier clinical finding that an anterolateral
cordotomy can alleviate chronic pain (Spiller and Martin
19 12), it has been widely accepted that the ventrolateral
quadrant of the spinal cord contains the main pathways
responsible for the transmission of the nociceptive infor-
mation that produces pain in both animals (Breazile and
Kitchell 1968; Kerr and Lippman 1974; Mehler et al. 1960;
Rossi and Brodal 1957; Torvik 1956; Valverde 196 1; Zem-
lan et al. 1978) and man (Bowsher 1957, 1962). The great
majority of fibers traveling in the ventrolateral quadrant of
the spinal cord terminate within the brain stem reticular
formation, whereas the remainder terminate mainly in the
thalamus. The relative contributions of the spinoreticular
and spinothalamic systems to nociception and pain are still
unclear and remain a matter of controversy. Furthermore,
on the basis of anatomic and electrophysiological data
from animals, some authors have suggested an additional
contribution of dorsolateral pathways to nociception (Ap-
karian et al. 1985, 1989; Hylden et al. 1986, 1989; Jones et
al. 1987; McMahon and Wall 1983, 1985).
With regard to the spinoreticular nociceptive systems,
we have recently suggested that medullary neurons located
in the rat subnucleus reticular-is dorsalis (SRD) could play
an important role in processing specifically nociceptive in-
formation. These neurons are unresponsive to visual, audi-
tory, or proprioceptive stimulation and are activated exclu-
sively by cutaneous A& or A& and C-fiber peripheral vol-
leys from any part of the body (Villanueva et al. 1988).
They very precisely encode the intensity of electrical, ther-
mal, and mechanical stimulation within the noxious range
(Villanueva et al. 1989a), and their A& and C-fiber-evoked
activities are depressed by systemic morphine in a dose-re-
lated and naloxone-reversible fashion (Bing et al. 1989).
Neurons presenting similar electrophysiological features
have been recorded recently in the medullary reticular for-
mation of monkeys (Cliffer et al. 1989).
The aim of the present study was to determine which
spinal ascending pathways are responsible for the activa-
tion of SRD neurons by making restricted sections of the
white matter of the spinal cord corresponding to the var-
ious ascending funiculi for which a role in nociception has
been suggested. A preliminary report of this work has ap-
peared in abstract form (Villanueva et al. 1989b).
METHODS
The methods were essentially similar to those described pre-
viously (Villanueva et al. 1988).
Animal preparation
Experiments were performed on 42 male Sprague-Dawley rats
weighing
220-300 g. After an intraperitoneal injection of 100 PLg
424 0022-3077/90 $1 SO Copyright 0 1990 The American Physiological Society
ASCENDING PATHWAYS AND SRD 425
atropine sulfate, the animals were deeply anesthetized with 2%
halothane in a nitrous oxide-oxygen mixture (2/3: l/3). A tracheal
cannula was inserted, the jugular vein was cannulated, and the
animals were paralyzed by intravenous injection of gallamine
triethiodide (Flaxedil) and artificially ventilated; the rate (70-80
strokes/min) and volume of ventilation were adjusted with the
use of a capnometer (Traverse Medical Monitors, MI) to main-
tain a normal acid-base equilibrium. Heart rate was continuously
monitored and core temperature maintained at 37 t OSOC by
means of a homeothermic blanket system.
The animals were mounted in a stereotaxic frame with the head
fixed in a ventroflexed position by means of a metallic bar ce-
mented to the skull, and the caudal medulla was then exposed by
removing the overlying musculature, atlantooccipital membrane,
and dura mater. Laminectomies were performed on vertebrae
C3-Cs to expose the cervical cord.
After surgery the level of halothane was reduced to 0.5% to
achieve a level of anesthesia that was adequate for ethical pur-
poses but did not excessively depress neuronal responses to nox-
ious stimuli. In this respect, we have previously reported that this
anesthetic regimen allows a stable level of anesthesia, under which
neither electroencephalographic arousal nor cardiovascular reac-
tions are observed during the application of strong stimuli (Ben-
oist et al. 1984; Le Bars et al. 1980; Weil-Fugazza et al. 1984).
Recordings
Unitary extracellular recordings were made with glass micropi-
pettes ( lo- 15 MIt) filled with a mixture of 5% NaCl and ponta-
mine sky blue dye.
Single-unit activity was amplified and fed into a window dis-
criminator, the output of which was connected to a tape recorder
and a multichannel analyzer (Tracer TN 17 lo), to allow further
processing of the data.
The micropipettes were inserted on the left side of the medulla,
1 .O-2.0 mm caudal to the obex, and 0.5-l .5 mm lateral to the
midline. Stability for the recordings was achieved by placing over
the surface of the medulla a glass frame that was held in position
with a micromanipulator and a
2%
Ringer-agar gel. Nonnoxious
and noxious electrical or mechanical search stimuli were used to
help isolate unitary activity, and neurons were classified on the
basis of their characteristic responses to different stimuli applied
to their peripheral receptive fields. Once a cell had been identified,
the extent of its receptive field was determined.
Only cells showing no alterations in spike amplitude or wave-
form during the complete experimental procedure were consid-
ered.
Experimental design
As described previously (Villaneuva et al. 1988, 1989a), two
populations of SRD neurons were recorded: neurons with total
and neurons with partial nociceptive convergence (TNC and
PNC neurons, respectively).
These neurons responded to natural and electrical stimulation
of widespread areas of the body. Electrical stimuli were delivered
through pairs of stainless steel stimulating electrodes inserted sub-
cutaneously into the cheeks, the extremities of the limbs, and the
tail. The effects of the repeated application of single, square-wave
stimuli (50 trials, 0.66 Hz, 2-ms duration) were analyzed using
poststimulus histograms (PSH) built with the use of the multi-
channel analyzer. One or two components were generally re-
vealed by such analysis; these components always had fixed la-
tencies. As previously described (Villanueva et al. 1988) these
25 N
I 0 500 ms I I
1
0 500 ms
FIG. 1. Schematic representation of experimental design. TNC or PNC neurons (see text) were recorded in left subnu-
cleus reticularis dorsalis. A& and C-fiber-evoked responses were elicited after supramaximal percutaneous electrical stimu-
lation of the extremity of either left or right hindpaw. These responses were analyzed by building poststimulus histograms
(50 trials). Such sequences were reiterated before and after (30-40 min) restricted lesions of the cervical spinal cord, e.g., left
hemisection in the present figure. Such an experimental protocol was aimed at determining I) ascending pathways involved
in the activation of SRD neurons and 2) crossed (-) or uncrossed (- - -) nature of these pathways.
426 BING, VILLANUEVA, AND LE BARS
components appeared earlier when triggered from the base-as
opposed to the tip-of the tail. The difference between the laten-
ties obtained from the two sites of stimulation indicated that
peripheral fibers responsible for the early and late peaks of activa-
tion had conduction velocities - 10 and 0.8 m/s, respectively.
According to Gasser and Erlanger (1927) and Burgess and Per1
(1973), these correspond to peripheral conduction velocities in
the A& and C-fiber ranges, respectively.
All SRD neurons responded with an early (A6) peak of activa-
tion from all areas of the body tested with the use of suprathresh-
old percutaneous electrical stimuli. The cells were classified as
TNC neurons when two peaks of activation (A6, C) were elicited
from all areas of the body. When one or several areas of the body
gave rise to only an early (Ah) component, the neurons were
classified as PNC.
The experimental procedure is shown schematically in Fig. 1.
After the determination of the thresholds for C-fiber activation,
the extremities of the hindpaws (toes 2-4) were stimulated at
suprathreshold intensities (-3 times threshold). Two control se-
quences were performed during which 50 stimuli were applied at
5-min intervals alternately to the right and the left hindpaws.
Identical sequences were recorded 30-40 min after section of the
cervical cord. For each sequence, the mean number of spikes was
calculated for both the earlier and-when present-the later
peaks of activation in the following fashion. For a given cell, a
window corresponding to each peak triggered by a supramaximal
stimulus was determined on the PSH. Thereafter, the mean num-
ber of spikes occurring during each window (-4-30 and loo-350
ms for the earlier and later peaks, respectively) was calculated by
constructing a PSH from the responses to 50 repetitive supra-
maximal stimuli.
Cervical sections
The dura was slit over the cervical spinal cord at the end of the
second set of control sequences, and a transversal lesion was made
under a dissecting microscope by cutting the cord with a lancet
diamond knife (A. Meyer) at C4-C5.
Postlesion sequences were carried out 30 min after the lesions
to minimize possible early changes induced by the surgery. Pre-
vious reports (Villanueva et al. 1986a,b) and postlesion sequences
that were identical to the controls indicated that this half-hour
period was sufficient in this respect. Figure 2 shows examples of
cervical sections in which the lesions included, respectively, the
dorsal columns, the dorsolateral funiculus, the ventrolateral fu-
niculus, and hemisection of the spinal cord.
Statistical analyses
Results were expressed as means + SE. The modifications of
the A& and C-fiber-evoked responses were expressed as percent-
ages of the control values obtained in the PSHs. Paired or un-
paired Student’s t tests were used for statistical analyses.
FIG.
2. Examples
of
100~pm-thick cervical sections Nissl stained
with cresyl violet, which allowed the reconstruction of
the total extent of
any
lesions on camera lucida drawings. A: lesion of dorsal columns. B: lesion of dorsolateral funiculus. C?
lesion of dorso- and ventrolateral parts of the cord. D: hemisection of left cervical cord. See Figs. 8,9, 11, and 5, respectively,
for complete reconstruction of these 4 lesions.
ASCENDING PATHWAYS AND SRD
42-l
5OOpm
FIG. 3. Locations of 2 neuronal types recorded within the subnucleus reticular-is dorsalis (SRD). Each neuronal type is
presented in a single schematic representation of a coronal section of the medulla, 1.5 mm caudal to obex. A: location of
neurons with total nociceptive convergence (TNC), mainly in the dorsomedial part of the SRD.
B:
location of neurons with
partial nociceptive convergence (PNC), mainly in the ventrolateral part of the SRD. C: key for anatomic structures. CC,
central canal; Cu, nucleus cuneatus; N caud V, trigeminal nucleus caudalis; SRD, subnucleus reticular-is dorsalis; SRV,
subnucleus reticularis ventralis; ST, solitary tract; Pyr, pyramidal decussation.
Histological
controls
cresyl violet or carmin. Cord lesions were reconstructed from
camera lucida drawings of the serial sections.
At the conclusion of the experiments, the recording sites were The experiments during which lesions of the left spinal cord
marked by electrophoteric deposition of pontamine sky blue, and were studied on the responses of TNC neurons are summarized in
the cervical spinal cord and medulla were removed and fixed by Fig. 14. The technique employed involved overlapping camera
immersion in a 10% Formalin solution for 72 h and then soaked lucida drawings for each series of experiments and plotting these
in a 30% buffered sucrose solution for 48 h. The samples were on a standardized schematic section of the spinal cord. In this
frozen, cut in serial 100~pm-thick sections, and Nissl-stained with scheme, the spinal cord was divided into four quadrants by dor-
25-
25 -
O- 0
LEFT HINDPAW
N
50 -
CONTROL
O-
500ms
50
30-40 min
after lesion
I
1
250 500ms
I
0
RIGHT HINDPAW
250 500ms
250 500 ms
FIG. 4. Example of effects of a left hemisection of the cervical cord on responses of a TNC neuron after supramaximal
percutaneous electrical stimulation of hindpaws. Poststimulus histograms (50 trials, 0.66 Hz) after the application of
square-wave pulses (2-ms duration).
Top:
A& and C-fiber control responses.
Bottom:
30-40 min after a hemisection of left
spinal cord
(botbjm middk),
responses elicited from the right hindpaw were completely blocked. By contrast, responses
elicited from left hindpaw were only slightly diminished.
428 BING, VILLANUEVA, AND LE BARS
soventral and a laterolateral lines that both passed through the
central canal.
RESULTS
General properties of’the recorded units
.
A total of 42 units were recorded within the left SRD. As
previously described (Villanueva et al. 1988), these were
activated by percutaneous electrical stimulation of any part
of the body. They could be divided into two categories: I)
“neurons with total nociceptive convergence” (TNC), i.e.,
those neurons driven by A6 and C-fiber activation from the
whole body (n = 36); and 2) “neurons with partial noci-
ceptive convergence” (PNC), i.e., those neurons driven by
A&fiber activation from the whole body but by C-fiber
activation from some areas only (n = 6). TNC neurons
appeared to be located more dorsomedially than PNC
neurons within the SRD (Fig. 3). ‘There was no overlapping
with trigeminal neurons, except for some convergent units
with large excitatory peripheral fields; the question of the
borderline between trigeminal and SRD neurons has been
discussed in a previous work (Villanueva et al. 1988).
The majority (27/36) of TNC neurons displayed sponta-
neous activity (mean 4.0 t 1.2 spikes/s) that consisted of
irregular discharges. Three out of six PNC units were also
spontaneously active (5.5 t 1.7 spikes/s).
Responses ofSRD neurons to electrical stimulation
The extremities of the hindpaws (toes 2-4) were stimu-
oj’thc hindp.aws
lated supramaximally with 2-ms square-wave pulses ap-
After percutaneous electrical stimulation of the contra-
lateral (right) hindpaw (2.9-fold C-fiber threshold), TNC
neurons gave responses to both peripheral A& and C-fiber
activation (see individual examples in Figs. 4 and 6): the
A&fiber peak had a mean latency of 11.8 t 0.7 ms and
consisted of 7.0 t 0.7 spikes/stimulus; the C-fiber peak had
a mean latency of 119.0 t 4.0 ms and consisted of 12.9 t
1.4 spikes/stimulus. The application of identical stimuli to
the ipsilateral (left) hindpaw evoked both A& and C-fiber
responses with mean latencies of 15.2 t 1.7 and 125.2 t
3.6 ms, respectively, and mean counts of 6.0 t 0.6 and
8.3 t 0.8 spikes/stimulus, respectively.
In the case of PNC neurons, the application of supra-
maximal percutaneous stimuli to the contralateral (right)
hindpaw (2.6-fold C-fiber threshold) gave responses to pe-
ripheral A&fiber activation (mean latency: 10.7 t 0.9 ms;
mean 9.1 t 1.9 spikes/stimulus) and to C-fiber activation
(mean latency 117.0 t 13.3 ms; mean 1 1.6 t 2.0 spikes/
stimulus). The application of percutaneous electrical stim-
uli of similar intensities to the ipsilateral (left) hindpaw
evoked only A&fiber responses with a mean latency of
15.6 t 0.4 ms and a magnitude of 3.9 t 1.5 spikes/stimu-
lus (see an individual example in Fig. 12).
Eflects of cervical lesions on TNC responses
.
We will present results successively concerning experi-
spinal cord and 2) hemisection of the right cervical spinal
ments in which TNC neurons were recorded in the left
SRD before and after 1) hemisection of the left cervical
cord; and restricted lesions disposed dorsoventrally and in-
cluding 3) the dorsal columns, 4) the left dorsolateral funic-
plied percutaneously.
A
LEFT HINDPAW
before after
% %
loo-
50-
0
RIGHT HINDPAW
before after
0 Ab - fiber response m C - fiber resDonse
ASCENDING PATHWAYS AND SRD 429
ulus, 5) the left lateral funiculus, and 6) the left ventrolat-
era1 funiculus.
Hemisections of the le@ cervical spinal cord
.
Figure 4 shows an individual example of the massive A&
and C-fiber-evoked responses of a TNC neuron after per-
cutaneous electrical stimulation of the extremity of the
hindpaws (control). It can be observed that the A& and
C-fiber responses elicited from the right hindpaw were
completely abolished after hemisection of the left cervical
cord, whereas those evoked from the left hindpaw were
only slightly diminished. These results were confirmed in
eight experiments (Fig. 5): the responses elicited from the
hindpaw contralateral (right) to the lesion were abolished,
whereas those evoked from the ipsilateral (left) hindpaw
were slightly, but not significantly, diminished.
Hemisections ofthe right cervical spinal cord
.
To further investigate the pathways involved in the acti-
vation of TNC neurons, we performed hemisections on the
right cervical cord. The individual example presented in
Fig. 6 shows that the A& and C-fiber responses elicited
from the left hindpaw were completely abolished after
hemisection of the right cervical cord, whereas those
evoked from the right hindpaw remained almost un-
changed. As in the previous series of experiments, the cu-
mulative results, illustrated in Fig. 7, show that responses
25
N
50 -
25 -
LEFT HINDPAW
250 500ms
0 250 500 ms
elicited from the hindpaw contralateral (left) to the lesion
were abolished, whereas those evoked from the ipsilateral
(right) hindpaw were not significantly modified.
Dorsal columns lesions
The cumulative data presented in Fig. 8 show lesions
including the dorsal columns that did not modify the A&
and C-fiber-evoked responses evoked from either hind-
paw: the postlesion responses were essentially the same as
the controls.
Dorsolateral funiculus lesions
.
In individual cases, the responses were not modified by a
lesion that included the left dorsolateral funiculus. These
observations are corroborated by the cumulative data pre-
sented in Fig. 9, where only a slight, but not significant (t6 =
2.06; P < 0. l), augmentation of the C-fiber-evoked re-
sponses from the hindpaw ipsilateral (left) to the lesion
could be observed.
Lateral funiculus lesions
.
In these series of experiments, we regrouped four experi-
ments during which the lateral funiculus was lesioned in
addition to the dorsolateral funiculus. As lesions of the
dorsolateral funiculus were found to be ineffective (pre-
vious section), it can be assumed that any modifications
observed would be due mainly to the additional lesioned
RIGHT HINDPAW
CONTROL
25
N
50
30-40 min
1 I
250 500ms
after lesion
’
500ms
FIG. 6. Example of effects of a right hemisection of the cervical cord on the responses of a TNC neuron after supramax-
imal percutaneous electrical stimulation of hindpaws (experimental design, presentation, and symbols as in Fig. 4). Note
that responses elicited from left hindpaw disappeared, whereas those elicited from right hindpaw were not modified after
right hemisection.
430
A
BING, VILLANUEVA, AND LE BARS
FIG. 7. Summary of results from 5 ex-
periments during which effects of a hemi-
section of right cervical spinal cord were
studied on the responses of TNC neuro ns
(presentation as in Fig. 5). A: extent of
B
%
100
50
0
RIGHT HINDPAW
individual lesions.
B:
mean results ob-
tained during these experiments. Note
LEFT HINDPAW
before after after that responses elicited from left hindpaw
before disappeared, whereas t hose elicited from
right hindpaw were not significantly mod-
%
100
50
0
fiber response m C - fiber response
ified after right hemisection (***, P <
0.00 1).
T
I Ab -
FIG. 8. Summary of results from 7 ex-
periments during which effects of a lesion
of dorsal columns were studied on the re-
B
RIGHT HINDPAW
sponses of TNC neurons (presentation as
in Fig. 5). A: extent of individual lesions. II:
LEFT HINDPAW
after 1 mean results obtained during these experi-
ments. Note the lack of effect of lesions.
before after before
% %
loo-
50-
0
1
T
-I-
T
I] Ab - fiber response - C - fiber response
ASCENDING PATHWAYS AND SRD 431
B
LEFT HINDPAW
before after
[1 Ab - fiber response
%
loo-
50-
0
RIGHT HINDPAW
before after
m C - fiber response
FIG. 9. Summary of results from 7 ex-
periments showing the lack of effect of a
lesion of dorsolateral funiculus on re-
sponses of TNC neurons (presentation as
in Fig. 5). A: extent of individual lesions.
B:
mean results obtained during these ex-
periments.
area. The cumulative results presented in Fig. 10 show that
the A&fiber responses elicited from the ipsilateral hindpaw contralateral hindpaw. Probably because of the small num-
ber of experiments in this series, the diminution was not
were not modified and that, although the responses evoked statistically significant in the case of the A&fiber-evoked
by C-fiber activation were slightly reduced, this was not
statistically significant (t3 = 1.85; n.s.). By contrast, these responses (t3 = 2.15; 0.05 < P < 0.1); however, the same
lesion did induce a very significant decrease in the C-fiber-
lesions strongly diminished the responses elicited from the evoked responses (t3 = 8.77; P < 0.01).
LEFT HINDPAW
before after
RIGHT HINDPAW
before after
**
FIG. 10. Summary of results from 4
experiments during which effects of a le-
sion of lateral funiculus were studied on
the responses of TNC neurons (presenta-
tion as in Fig. 5). A: extent of individual
lesions: in all cases, a slight portion of lat-
era1 funiculus was sectioned.
B:
mean re-
sults obtained during these experiments.
Note the large reduction in responses elic-
ited from the contralateral hindpaw,
whereas no significant modifications of
the responses from the ipsilateral hindpaw
were observed (**, P < 0.0 1).
m C - fiber response
[ 1 Ab - fiber response
432 BING, VILLANUEVA, AND LE BARS
A
B
%
100
50
0
@a
Q
LEFT HINDPAW
before after
**
I
r] Ab - fiber response
25
LEFT HINDPAW
0
250 500
ms
1
0
250 500
ms
%
100
50
0
FIG. 11. Summary of results from 5
experiments during which effects of a le-
sion of ventrolateral quadrant were stud-
ied on the responses of TNC neurons (pre-
sentation as in Fig. 5). A: extent of individ-
RIGHT HINDPAW
ual lesions.
B:
mean results obtained
during these experiments. Note clear dim-
before after inution of the C-fiber responses elicited
from ipsilateral hindpaw and abolition of
responses from contralateral hindpaw (**,
P < 0.01; ***, P < 0.001).
m C - fiber response
RIGHT HINDPAW
N
CONTROL
50-
25-
O-
N
50
30-40 min
after lesion
m
25
0
0
il
250 500
ms
1” 1 111 . .
0
250 500
ms
FIG. 12. Example of effects of a lesion involving ventrolateral funiculus on the responses of a PNC neuron after
supramaximal percutaneous electrical stimulation of the hindpaws (presentation as in Fig. 4). Note complete blockade of
responses elicited from contralateral hindpaw and lack of effects on responses elicited from ipsilateral hindpaw.
ASCENDING PATHWAYS AND SRD 433
A
B
LEFT HINDPAW
%
100
50
0
T
%
100
50
0
I] Ab - fiber response m C - fiber response
before after
FIG. 13. Summary of results from 6 experiments dur-
ing which effects of a lesion of ventrolateral funiculus were
-
studied on the responses of PNC neurons (presentation as
in Fig. 5). A: extent of individual lesions. B: mean results
RIGHT HINDPAW
obtained during these experiments. Note lack of effect on
A&fiber-evoked responses elicited from ipsilateral hind-
before after paw an
elicited d abolition of A&
from contralateral and C-fiber-evoked
hindpaw. (***, P < 0 responses
.ooo 1).
Ventrolatcral fkniculus lesions
.
In this series of experiments, we included those during
which the ventrolateral funiculus was lesioned. In all five
units studied (Fig. 1 l), a lesion including the external part
of the ventrolateral funiculus completely abolished the re-
sponses elicited from the contralateral (right) hindpaw
while inducing only a diminution of the responses elicited
from the ipsilateral (left) hindpaw. With regard to the con-
tralateral hindpaw, depressions of 89.2 t 5.5% and 96.4 t
1.7% were observed for the A& and C-fiber-evoked re-
sponses, respectively (t4 = 14.56, P < 0.00 1; and t4 = 37.27,
P < 0.001, respectively). The responses elicited from the
ipsilateral hindpaw were less diminished: the A& and C-
fiber peaks were depressed by 22.6 t 9.5% and 36.5 t
6.7%, respectively, with the latter being statistically signifi-
cant
(t4
= 2.09, 0.1 < P < 0.2; and t4 = 5.09, P < 0.01,
respectively).
Eflixts of cervical lesions on PNC responses
c .
In this last series of experiments, we only tried to verify
whether or not the ascending pathways responsible for the
activation of PNC neurons were similar to those found to
activate TNC neurons. Thus we will present data only re-
lated to experiments during which lesions did modify PNC
neuronal responses. Figure 12 shows a typical example of a
PNC neuron that, during the control period, gave A& and
C-fiber-evoked responses after supramaximal percutane-
ous electrical stimulation of the contralateral (right) hind-
paw, whereas the stimulation of the ipsilateral (left) hind-
paw elicited only A&fiber-evoked responses. After a lesion
including the dorsolateral, lateral, and ventrolateral funic-
uli, the responses elicited from the contralateral hindpaw
were completely abolished, whereas the A&fiber-evoked
responses from the ipsilateral hindpaw remained un-
changed. As illustrated in Fig. 13, this was a consistent
finding: the lesions presented in this figure completely
blocked the responses elicited from the contralateral hind-
paw (A&fiber response: t5 = 9.82, P < 0.00 1; C-fiber re-
sponse: t5 = 46.18, P < 0.001) without modifying the
A&fiber-evoked response elicited from the ipsilateral
hindpaw.
DISCUSSION
The present study demonstrates that the ascending fibers
responsible for the activation of SRD neurons are confined
to a part of the white matter of the spinal cord that classi-
cally has been implicated in the transmission of nocicep-
tive information and in pain. This assertion is supported by
1) the lack of modification of SRD neuronal responses after
lesions including the dorsal and dorsolateral regions of the
cervical spinal cord and 2) the large reduction and block-
ade of these responses after lesions of the lateral and ven-
trolateral quadrant, respectively. After considering some
methodological aspects of the study, the discussion will
focus on the participation in the activation of SRD units,
pathways that might have a role in the transmission of
nociceptive information from the spinal cord to the brain.
Methodological considerations
We were obliged to perform “acute” lesions of the spinal
cord, rather than “chronic” lesions made several days be-
434 BING, VILLANUEVA, AND LE BARS
fore the recording sessions, because of the existence of two
neuronal populations within the SRD, namely TNC and
PNC neurons (Villanueva et al. 1988, 1989a): after chronic
lesions, some situations could have occurred during which
we would have been unable to distinguish between the two
classes of neuron. From a more general viewpoint, the
great advantage of acute lesions performed in a standard-
ized paradigm lies in the comparison of the responses of the
same neuron before and after the lesions. The acute surgi-
cal procedure did not seem to introduce a bias in our re-
sults because SRD neuronal responses were found not to be
modified after several lesions; in particular, large lesions
such as hemisections of the cord produced on the same
neuron either a blockade of the neuronal activity or a lack
of effect, depending on the part of the body stimulated.
Previous studies (Villanueva et al. 1986a,b) have also
shown that a half-hour period after cord section is suffi-
cient to minimize possible changes because of the surgical
procedure itself.
Involvement of’dorsal pathways
.
On the basis of the present results, it is possible to ex-
clude the participation of several ascending pathways for
which a role in nociception has been suggested: the post-
synaptic dorsal columns (Angaut-Petit 1975a,b; Giesler et
al. 1984, 1985; Uddenberg 1968) and the spinocervical
tract traveling within the dorsolateral funiculus (Craig and
Tapper 1978; Giesler et al. 1979a; Kajander and Giesler
1987; Lundberg and Oscarsson 196 1; Morin 1955). More
surprisingly, in view of the preferential or exclusive respon-
siveness of SRD neurons to noxious inputs (Villanueva et
al. 1988) our data also suggest that nociceptive lamina I
spinal neurons do not contribute to a great extent to the
spinal input onto SRD neurons because it has been shown
that, in rats, they project to medullary levels mainly via the
most dorsal parts of the contralateral dorsolateral funiculus
(McMahon and Wall 1985). For the same reasons, partici-
pation of collaterals of the spinomesencephalic and spino-
thalamic projections of lamina I neurons traveling in the
dorsolateral funiculus (Apkarian et al. 1985, 1989; Hylden
et al. 1985, 1986, 1989; Jones et al. 1985, 1987; McMahon
and Wall 1983, 1985; Swett et al. 1985) seems unlikely.
However, these neurons cannot be completely excluded in
this respect because some lamina I nociceptive neurons
seem to project in the most lateral parts of the rat’s dorso-
lateral funiculus (McMahon and Wall 1985). In addition, it
has been found that large lesions of the dorsolateral funicu-
lus do not completely abolish the supraspinal projections
of lamina I neurons (Apkarian and Hodge 1989; Hylden et
al. 1989). Thus it is conceivable that some lamina I projec-
tions travel through the most lateral parts of the lateral
funiculus, lesions of which reduced SRD neuronal re-
sponses elicited from the contralateral hindpaw. Such lam-
ina I neurons could, therefore, contribute-to some extent
-to the activation of SRD neurons.
The only apparent effect of dorsolateral funiculus lesions
was a slight but not significant augmentation of the C-fiber
responses evoked from the hindpaw ipsilateral to the le-
sion. These effects could be due to a lifting of tonic de-
scending inhibitorv influences acting on the dorsal horn
because we have previously shown that the acute disrup-
tion of a single dorsolateral funiculus induced a facilitation
of the C-fiber-evoked responses of dorsal horn convergent
neurons ipsilateral to the lesion (Villanueva et al. 1986a). It
should be noted, however, that such facilitatory effects
were not seen after larger sections of the cord that included
the dorsolateral funiculus (e.g. see Fig. 5,7, 10, 11); in these
cases, mixtures of excitatory and inhibitory influences
might mask each other.
Involvement ofventral pathways
Figure 14 summarizes the lesions made on the ipsilateral
(left) side of the spinal cord while recording from TNC
neurons. In each category, the total extent of the lesions is
shown by the overlapping of individual lesions. Ineffective
lesions are illustrated in Fig. 14,
a
and
b,
corresponding to
the dorsal columns and the dorsolateral funiculus, respec-
tively; partially effective lesions are illustrated in Fig. 14c,
corresponding to the lateral funiculus; and totally effective
lesions are illustrated in Fig. 14,
d
and e, corresponding to
the ventrolateral funiculus and hemisections, respectively.
Because the first and last two figures correspond to totally
ineffective or totally effective lesions, respectively, and as-
suming that the gray matter is not involved in the trans-
mission of information toward the SRD, the actual effec-
tive zones were drawn by subtracting c - a - b, d - a - b -
c, and d - a - b. This is shown on the
right
of Fig. 14. Note
that the white matter, which contained fibers activating
ipsilateral TNC neurons from the contralateral hindpaw, is
tightly restricted to the lateral and ventrolateral funiculi.
One cannot exclude the possibility that the lesions inter-
fered with tonic facilitatory drives or descending controls
of spinal circuits, thus regulating ascending information in
other pathways. In addition, ventral quadrant lesions were
never made in isolation, but always with dorsal lesions; as
stated above, lesions of a mixture of excitatory and inhibi-
tory influences might therefore mask each other. Although
these possibilities cannot be formally ruled out, it seems
very likely that the explanation of our results is to be found
mainly in a specific blockade of nociceptive informations
traveling through ascending “pain pathways.”
According to the literature, two ascending pathways in-
volved in nociception travel through the ventrolateral
quadrant: the lateral spinothalamic tract (Boivie 1979;
Giesler et al. 1979b; Kerr and Lippman 1974; Mehler
1969; see also references in Vierck et al. 1986) and the
spinoreticular tract (Breazile and Kitchell 1968; Kerr 1975;
Mehler 1969; Mehler et al. 1960; Torvik 1956; Zemlan et
al. 1978). In man (Walker 1940; White and Sweet 1969)
and monkeys (Applebaum et al. 1975), the fibers of the
spinothalamic tract are somatotopically organized, with
the most caudal/distal parts of the body represented in the
lateral part of the ventrolateral quadrant. The possibility of
such an organization for the spinal paths projecting toward
the SRD is possible, as lesions including this area com-
pletely blocked SRD responses evoked from the extremity
of the contralateral hindpaw.
In rats, the fibers of the lateral spinothalamic tract are
confined to the ventrolateral quadrant (Giesler et al. 198 1);
thus the possibilitv exists that the SRD is one of the collat-
ASCENDING PATHWAYS AND SRD 435
b
-.
i
c-a-b
FIG. 14. Summary of experiments during which
I effects of lesions of different spinal pathways on the
i
c
responses of TNC neurons after stimulation of the
i
i contralateral hindpaw were studied. Lc$: different
i series of experiments are illustrated by overlapping of
-. .-.- .-.-. .-.-. .-.-.-. .-
k i
d-a-b
maximal extension of lesions shown by shaded areas.
i U: overlapping of ineffective lesions including dorsal
i columns (see Fig. 8). h: overlapping of ineffective
i lesions including left dorsolateral funiculus (see Fig.
d-a-b-c
9). c’: overlapping of partially effective lesions includ-
ing left lateral funiculus (see Fig. 10). d: overlapping
of completely effective lesions including left ventro-
lateral funiculus (see Fig. 1 1). c: overlapping of com-
i
i pletely effective hemisections of left spinal cord (see
Fig. 5). Right: reconstruction within white matter of
“effective” regions, that is, those able to diminish or
block responses elicited from contralateral hindpaw.
c - a - b: lateral funiculus (partially effective); d -
a - b - c: ventrolateral funiculus; d - a - b: lateral
plus ventrolateral funiculi (completely effective).
i
era1 targets of the lateral spinothalamic tract. Further in-
vestigation in this respect merits consideration because
collateralization of the spinothalamic system to medullary
reticular structures has been demonstrated previously in
the rat (Kevetter and Willis 1983) as well as to other retic-
ular areas in different species (see references in Kevetter
and Willis 1984).
It has been shown that the ventral spinoreticular system
terminates in the most caudal parts of the brain stem
(Bowsher 1957, 1962; Breazile and Kitchell 1968; Mehler
et al. 1960; Torvik 1956; Zemlan et al. 1978), including the
SRD in the rat (Torvik 1956). Spinal projections to medul-
lary reticular nuclei have also been shown (Nahin 1987),
and we recently observed the labeling of numerous neurons
at various levels of the spinal cord after small injections of
retrograde tracers within the SRD (De Pommery et al. un-
published data). We therefore suggest that, in addition to
other medullary reticular areas such as the lateral reticular
nucleus and the subnucleus reticular-is ventralis (Zemlan et
al. 1978), rat SRD neurons are among the direct targets of
the ventral spinoreticular tract. That the former two areas
contribute indirectly to the activation of SRD neurons
seems unlikely because 1) the majority of the spinal units
backfired from the rat lateral reticular nucleus do not share
the electrophysiological features of SRD neurons
(Menetrey et al. 1984) and 2) the majority of subnucleus
reticularis ventralis neurons are not activated by noxious
inputs (Villanueva et al. 1988). In fact, these structures
have been shown to be involved in cardiovascular controls
and spinoreticulocerebellar loops (for a review, see, respec-
tively, Ciriello et al. 1986; Oscarsson 1973).
Both anatomic and electrophysiological studies indicate
that the brain stem reticular nucleus gigantocellularis
(NGC), a region rostra1 and medial to the SRD, receives
dense projections from the ventral spinoreticular tract
(Bowsher 1957, 1962; Breazile and Kitchell 1968; Casey
1969; Mehler et al. 1960; Zemlan et al. 1978); and, indeed,
lesions of the ventrolateral quadrant strongly reduce so-
matic responses of NGC neurons (Casey 1969). Knowing
these facts, one could envisage mutual interactions be-
tween SRD and NGC neurons, that is, the activation of
NGC as the result of the activation of SRD or vice versa.
However, such a possibility seems unlikely because the spi-
nal neurons projecting to NGC and responding to noxious
436 BING, VILLANUEVA, AND LE BARS
stimulation do not share the general electrophysiological the effects described herein, these influences could be re-
features of SRD neurons: spinal NGC projecting neurons lated to reticulospinal excitatory systems, most of which
exhibit irregular responses after natural stimulation and have been reported to travel in the ventrolateral or ventral
poor encoding capacities for noxious events (Fields et al. funiculi (Basbaum et al. 1978; Martin et al. 1978; Nyberg-
1977; Haber et al. 1982; Maunz et al. 1978; Thies and Hansen 1965; Skagerberg and Bjorklund 1985).
Foreman 1983); similar irregular responses after peripheral
stimulation have been observed from NGC neurons them- Functional potentiality qf’pathways relaying in SRD nuclei
selves (Casey 1969; Gokin et al. 1977; Goldman et al. 1972;
Guilbaud et al. 1973; Le Blanc and Gatipon 1974; Pearl
and Anderson 1978). These observations contrast greatly
with the reproducibility of responses and the exquisite en-
coding properties of SRD neurons (Villanueva et al. 1988,
1989a). It is difficult, however, to conclude with certainty
that SRD and NGC neurons do not interact with each
other: anatomic and physiological data concerning this
matter are lacking, and we have not studied the total ros-
trocaudal extension of TNC and PNC neurons in our ex-
perimental conditions. Because NGC neurons have not
previously been recorded in the same species under an
identical anesthetic regime, such information is an abso-
lute prerequisite before any definitive conclusion can be
drawn.
Taken as a whole, the present results are in good agree-
ment with the anatomic observations that the great major-
ity of fibers traveling through the ventrolateral quadrant of
the spinal cord terminate within the brain stem reticular
formation. More generally, they are in keeping with all data
that emphasize the involvement of the ventrolateral funic-
ulus in nociception and pain (see references in Vierck et al.
1986). In this respect, one might recall that cordotomies in
man, involving lateral and ventrolateral parts of the spinal
cord, produce a long lasting attenuation of pain from a
contralateral focus (Nathan and Smith 1979); interestingly,
lesions including the most ventral parts of the ventrolateral
quadrant do not increase the effectiveness of ventrolateral
cordotomy (see Vierck et al. 1986). Also, lesions of the
anterolateral quadrant strongly reduce pain-related reac-
Involvement ofcrossed ventral pathways
I
Our data demonstrated that the ascending fibers respon-
sible for the activation of SRD neurons cross the midline
below the cervical cord (C,-C,) and travel within the ven-
trolateral quadrant regardless of whether the contralateral
or the ipsilateral hindlimb is stimulated. In the latter case,
this implies that the signals travel by a complex double-
crossed pathway before they reach SRD neurons. This
would be in keeping with our previous (Villanueva et al.
1988) and present findings that the activation of SRD
neurons from contralateral parts of the body consistently
occurs at shorter latencies than are obtained when ipsilat-
tions in monkeys (Vierck et al. 1986). By contrast, lesions
of the dorsal columns have not elicited unequivocal effects
in animals and man: slight decreases in pain reactivity in
cats and monkeys (Casey and Morrow 1988; Vierck et al.
197 l), and no relief but rather an increase in pain reactivity
in humans (Nathan et al. 1986). Finally, lesions of the
dorsolateral funiculus have been found to increase respon-
siveness to noxious stimulation in animals (Casey and
Morrow 1988; Davies et al. 1983; Vierck et al. 197 1).
In conclusion, our data reinforce the idea that SRD
could participate in processing specifically nociceptive in-
formation. The existence of both crossed and double-
crossed pathways relaying in this structure indicates that
era1 areas are stimulated. As in our previous report (Villa- the organization of spinoreticular nociceptive pathways is
nueva et al. 1988) this difference in latencies was -3 ms in more complex than expected, at least in the rat. Further
the present study. This suggests that the double-crossed studies are needed to determine the exact nature of the
pathway contains very few synapses-three at the very double-crossed pathway.
most and probably fewer. Together with the similarity of
TNC neuronal responses elicited from one part of the body
We thank Dr. S. Cadden for advice in the preparation of the manuscript,
and from its contralateral homologue, these observations
J. Carrouk for the histology, E. Dehausse for drawings and photography,
suggest that the crossed and double-crossed pathways
and M. Cayla for secretarial help.
This work was supported by 1’Institut National de la Santk et de la
might share a symmetrical neuronal network. Whether the
Recherche Medicale (INSERM) and la Direction des Recherches et Etudes
double-crossed pathway is sustained by brain stem collat-
Techniques (DRET). Dr. Z. Bing was supported by a scholarship from the
era1 projections of the crossed pathway or by relays in other
French government.
structure(s), we cannot say on the basis of the present data.
Address for reprint requests: L. Villanueva, Institut National de la Sante
et de la Recherche Medicale, Unite de Recherches de Physiopharmacolo-
gie de Systeme Nerveux, - 7 rue d’Alesia, Paris 750 14, France.
Involvement of ipsilateral ventral pathways
Received 3 1 July 1989; accepted in final form 17 October 1989.
In addition to crossed and double-crossed pathways, our
results also suggest the existence of a small group of fibers
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