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Electrophysiological evidence for a role of the anterolateral quadrant of the spinal cord in the transmission of noxious messages to the thalamic ventrobasal complex in the rat
Brain Research, 342 (1985) 77-84 Elsevier
77
BRE 10958
Electrophysiological Evidence for a Role of the Anterolateral Quadrant of the Spinal Cord in the Transmission of Noxious Messages to the Thalamic Ventrobasal Complex in the Rat MARC PESCHANSKI, ANNIE BRIAND, MICHI~LE GAUTRON and GISE,LE GUILBAUD Unit( de Recherches de Neurophysiologie Pharmacologique, U 161 INSERM, Paris 75014 (France)
(Accepted December 4th, 1984) Key words'." nociception - - thalamic VB neurons - - spinal pathways - - anterolateral quadrant
Responses to noxious mechanical and thermal stimulation applied to the hindpaws were recorded extracellularly from the same neurons of the ventrobasal complex of the rat thalamus (VB) before and after lesions of various areas of the cervical cord in order to determine the pathways carrying the afferent messages. It was demonstrated that lesions of the dorsal and dorsolateral portions of the cord failed to eliminate the VB neuronal responses to noxious stimulation. By contrast, lesion of one anterolateral quadrant eliminated the responses to a noxious stimulation applied to the hindpaw contralateral to the lesion. This occurred whether the lesion was ipsilateral or contralateral to the recording site. From the present study and the data in the literature, it is concluded that the fibers of the spino-thalamic tract which are completely crossed in the spinal cord, travel in the anterolateral quadrant and project directly onto the VB, are involved in the transmission of noxious messages from the cord to the VB neurons. This conclusion indicates that the VB neuronal responses to noxious stimulation of the hindpaw ipsilateral to the recording site depend on the spinothalamic projection to the opposite ventrobasal complex. This therefore suggests that some noxious messages which reach a particular VB neuron are conveyed via the opposite VB and the existence of a thalamo-cortico-thalamic loop is discussed.
INTRODUCTION
presence of terminals of the spinothalamic tract in this area 19,2o,27,35. However, it is difficult to reconcile
In their classical study, Poggio and Mountcastle 29
the anatomical data showing that the spinal projec-
demonstrated the presence of n e u r o n s activated by noxious stimulation in the posterior nuclear group (PO) of the cat thalamus, and claimed that these responses were associated with the existence of spino-
tions are strictly crossed and somatotopically organized in the VB with the characteristics of the receptive fields of VB noxious responsive neurons which are often large and symmetrically bilateral, with only
thalamic projections to this nucleus. F u r t h e r anatomical studies showing that spinal afferents could be demonstrated in this area in the cat ~,3 but not in the adjacent ventroposterior nucleus supported this hypothesis, underlining the possible role of the fiber paths in the anterolateral quadrant of the spinal cord in the transmission of noxious messages towards su-
a poor somatotopic organization (see discussion in ref. 25). This paradox led us to suggest that 'noxious inputs relayed by other pathway(s) than the spinothalamic tract had to be hypothesized '25. Amongst the pathways conveying noxious messages and originating from the spinal cord, 3 other ascending pathways could be considered (see references in refs, 2, 32): the spino-reticular system, the spino-cervico-thalamic path and the postsynaptic dorsal column system. The present experiment was therefore designed to determine whether the participation of one or more of these other pathways could explain some of the results obtained at the VB level.
praspinal structures. In the ventrobasal complex (VB) of the rat thalamus, we have observed n e u r o n s responding to noxious stimuli intermingled with n e u r o n s responding exclusively to non-noxious stimuli 13. This result again corresponds to the anatomical demonstration of the
Correspondence: M. Peschanski, Unit6 de Recherches de Neurophysiologie, U 161 INSERM, 2 rue d'Aldsia, Paris 75014, France.
0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
7~ The present study is based upon the extracellular recording of responses of the same VB neurons before and after successive restricted lesions of the spinal cord. The results of these experiments were analyzed taking into account the experimental data establishing that in the rat, the spinothalamic afferents to the lateral thalamus are strictly crossed 27 and travel in the anterolateral quadrant11 while the spino-reticular pathways travel in the same area but are both crossed and direct 4. By contrast, the two main remaining systems (spino-cervical tract and postsynaptic fibers of the dorsal columns) are uncrossed and ascend, respectively, in the dorsolateral and dorsal portions of the cord10,12. MATERIALS AND METHODS 24 Male Sprague-Dawley albino rats weighing between 240 and 300 g were anesthetized with a gaseous mixture of fluothane in nitrous oxide (2/3) and oxygene (1/3), paralyzed with an i.v. injection of gallamine triethiodide and artificially ventilated using a Palmer pump. The surgical preparation was made under deep anaesthesia using fluothane at a concentration of 3% which was then lowered to 0.5-0.6% and maintained at this level during the recording period. The level of anaesthesia was systematically checked by an electrocorticogram recorded longitudinally between two silver ball electrodes applied on the dura mater at the level of the frontal and occipital cortex. Under these conditions, the ECoG consisted of theta monomorphic waves of 4-5 Hz, 100-120 ~V associated with a few spindles of 1214 Hz. It was checked at the beginning of the experiments that noxious stimuli did not induce arousal reactions on the ECoG. The vascularization of the skin was checked by observing the colour of the extremities and their ability to return quickly to the previous state after application of pressure. The central temperature was maintained between 37 and 38 °C using a homeothermic blanket system.
Recording procedures A small craniotomy was made in the left part of the skull at the level of the VB as defined in previous experiments ~3, and the dura mater removed. The recording electrodes (10-15 Mff2) were glass micropipettes filled with a mixture of 5% NaC1 and ponta-
mine sky blue. The iontophoretic application of dye before the sacrifice and perfusion of the animal with formalin allowed the location of the recording site oil Nissl-stained sections of the VB. The VB neurons were characterized by their responses to mechanical stimulation, either non-noxious (brushing, strokes, pressure) or noxious (pinches) and to noxious thermal stimulation (plunging the paw in a 50 °C water bath) and their receptive fields were mapped. The interval between two successive noxious stimuli was 3 rain to limit the effects of sensitization and/or desensitization (see discussion in ref. 24). In the present study, 15 neurons were studied, responding to noxious stimulation either exclusively (n = 13) or, in two cases, with an additional response to non-noxious stimuli (convergent neurons). Their receptive fields for noxious stimulation included both hindpaws. Four other VB neurons responding exclusively to non-noxious stimulation applied to a restricted receptive field contralateral to the recording site were used as controls for possible non-specific effects of the spinal sections on the responses of VB neurons.
Experimental protocol During the surgical procedure, the skin and muscles overlying the cervical vertebrae were cut and access to the cord gained by two or three laminectomies usually including vertebrae C3. C5 and C7. The spinal cord was left exposed but covered with saline. Once a neuron had been characterized by repetitive noxious and non-noxious mechanical and noxious thermal stimuli applied to both hindpaws, a lesion of a portion of the spinal cord was performed using either a small sharp knife or a lancet diamond knife (A. Meyer Co.). It was checked that slitting the dura mater overlying the spinal cord did not modify the size or the shape of the spikes. In some of the noxious neurons, opening the dura was accompanied by a neuronal discharge which could be interp.reted as a response to a noxious stimulation since "control' neurons responsive only to non-noxious stimulation did not exhibit this reaction. We only analyzed the neuronal responses at least 10 rain after the lesion had been performed to avoid the interference of possible non-specific reactions related to vegetative phenomena. It can be noted, however, that neither tachycardin nor changes of the ECoG recording were ob-
79 served. Responses of the neuron to the different stimuli applied r e p e a t e d l y on both hindpaws were analyzed at least during 30 min following the lesion. A second and in some cases a third lesion of the spinal cord could be p e r f o r m e d following the same protocol to study the responses of the same neuron after successive cutting of different spinal pathways. In these cases of multiple lesioning, each lesion was made at a different spinal level in o r d e r to allow clear interpretation of the histological data concerning their extent and location in the cord. The histological analysis was m a d e on 100-/~m thick sections cut serially on a freezing m i c r o t o m e and Nissl-stained with cresyl violet. The complete extent of each lesion was d e t e r m i n e d by superimposing
using a camera lucida, the drawings of the serial sections containing parts of the lesion. As can be seen in Fig. 1, it was possible to obtain relatively selective lesions of the dorsal columns (Fig. 1A) or of the dorsolateral funiculus on one side (Fig. 1B). Lesions of the anterolateral quadrant often encroached upon the lateral column and, due to the difficulty of maintaining a stable recording during the spinal lesions, it was not possible, in our experimental conditions, to perform a selective lesion of the anterolateral quadrant (Fig. 1C). Finally, complete hemisections (Fig. 1D) could be produced. No strict protocol was followed with regard to the o r d e r of the lesions in o r d e r to avoid bias.
D
Fig. 1. Photomicrographs of 4 different examples of spinal lesions performed during the study. A: lesion of the dorsal columns. B: Icsion of the dorsolateral funiculus. C: lateral lesion involving mostly the anterolateral quadrant. D: hemisection. The sections presented here are those including the largest lesion in each case, but reconstruction of the complete lesions using the camera lucida extcnded them a little, although these are representative examples of the series.
Left Paw
RESULTS
~,,
Right Paw
All sites of i o n t o p h o r e t i c applications of p o n t a mine sky blue w e r e r e c o v e r e d and c o n f i r m e d that all the units r e c o r d e d w e r e located in the rostral p o r t i o n of the lateral VB. As d e s c r i b e d in a p r e v i o u s study ~3, no t o p o g r a p h i c a l s e g r e g a t i o n of n o x i o u s vs n o n - n o x ious r e s p o n s i v e or ' c o n v e r g e n t '
neurons
was ob-
served.
fl 50
Pinch
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In all 4 ' c o n t r o l ' n o n - n o x i o u s r e s p o n s i v e n e u r o n s ,
I
50
Pinch
the r e s p o n s e s to p e r i p h e r a l s t i m u l a t i o n of the r e c e p tive field w e r e not r e d u c e d as long as the dorsal col-
lOHz t
u m n p a t h w a y c o n t r a l a t e r a l to the r e c o r d i n g site was intact, e v e n w h e n m o s t o t h e r areas of the c o r d w e r e d e s t r o y e d by successive cuts. This finding d e m o n strates that the p r o c e d u r e we used allows the spinal p a t h w a y for a p a r t i c u l a r type of m e s s a g e to be d e t e r m i n e d w i t h o u t any o b v i o u s non-specific effects of spinal section. T h e results o b t a i n e d f r o m the 15 n e u r o n s r e s p o n sive to n o x i o u s s t i m u l a t i o n strongly suggest the inv o l v e m e n t of the a n t e r o l a t e r a l q u a d r a n t of the c o r d in the t r a n s m i s s i o n of n o x i o u s inputs t o w a r d t h e V B . In 7 cases (5 n o x i o u s n e u r o n s and the 2 ' c o n v e r g e n t '
I 5O
tl
;
it
50
Pinch
tl
Pinch
Fig. 3. Series of peristimulus histograms showing the effects of a spinal hemisection performed on the same side as the recording site as indicated in the scheme. Responses to a pinch of the hindpaws (arrows) and a noxious thermal stimulus (50 °C water bath) are indicated on the top trace for the controls, on the left side for the left paw, on the right side for the right paw, Bottom trace shows the responses of the same VB neuron to the same noxious stimuli 10-30 min after the section.
n e u r o n s ) , it was n o t possible to e l i m i n a t e the activation of the n e u r o n s by s t i m u l a t i o n of e i t h e r h i n d p a w despite large cuts in the spinal cord. It was f o u n d , during histological c o n t r o l s , ~hat t h e s e cuts n e v e r inv o l v e d a c o m p l e t e half of the spinal cord, always leaving u n t o u c h e d at least the a n t e r o l a t e r a l q u a d r a n t
right hindpaw 50oc
(Fig. 2). Lesions of the dorsal cord, d o r s o l a t e r a l fu-
L
a
i
b
c~d
~2
t~
c
d
Fig. 2. a-e: camera lucida drawings showing the lesions reconstructed from serial 100/~m Nissl-stained sections in cases where no clear effect of spinal lesions of the VB neuronal responses to noxious stimulation could be observed. In e, the scheme shows a composite superimposition of the various examples, to show the total extent of spinal lesions which did not modify the receptive fields of the VB noxious responsive neurons.
5Hz Fig. 4. Series of peristimulus histograms showing the effects ol successive lesions of the dorsal ( l 2), dorsolateral (3) and lateral (4) cervical cord (respectively at C5. C3 and C7) on the rcsponse of the same VB neuron to noxious pinch of the hindpaw contralateral to the 1ast lesion (lateral).
81 niculus, lateral column or anteromedial tract were ineffective in modifying the receptive fields of the noxious responsive VB neurons. It can be underlined that this result applies also to the responses to nonnoxious stimulation in the two 'convergent' neurons which did not disappear after lesions destroying most of the dorsal part of the cord. Results obtained in the 8 other neurons exclusively activated by noxious stimulation were similar whatever the order of the lesions. Figs. 3, 4 and 5 are representative examples of these results obtained using either mechanical or thermal noxious stimuli. Cuts in any part of the dorsal cord, i.e. dorsal columns, Lissauer's tract or dorsolateral funiculus failed to eliminate the neuronal responses to noxious stimuli applied to either hindpaw (Fig. 4). A further lesion of one anterolateral quadrant of the cord eliminated completely the response of the neuron to noxious stimuli applied to the hindpaw contralateral to the lesion site. In complete contrast, the neuronal responses elicited by noxious stimulation applied to the hindpaw contralateral to the unlesioned anterolateral quadrant was preserved, whether this part of the receptive field was contralateral (Fig. 3) or ipsilateral (Fig. 5) to the recording site. The elimination of a part of the receptive field of a particular neuron was most often the only clear alteration of its response following multiple lesions, and this was observed as
Left Paw
Right Paw
I
{
II
tl
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t l
'1(
t l
Fig. 5. Series of peristimulus histograms showing the effects of a spinal hemisection performed on the side contralateral to the recording site. Legend as in Fig. 2.
long as the recording of the neuronal activity was continued, which could be more than 60 min after the lesion in most cases. In 5 other cases, not considered above, the neurons which had been tested before the lesion of the cord were lost during or just after hemisection of the cord ipsilateral to the recording site. In these cases, other noxious responsive neurons were recorded after the lesion, exhibiting a completely unusual feature in that they responded to noxious stimuli applied to the hindpaw ipsilateral to the recording site but not to that contralateral to it while receptive fields of VB noxious neurons are, in normal rats, either contralateral or bilateral but not ipsilateral to the recording sitel3. DISCUSSION The present electrophysiological study demonstrates that, in the rat, neuronal responses to noxious stimuli recorded in the thalamic ventrobasal complex depend upon the integrity of, at least, an anterolateral quadrant of the spinal cord. Indeed, although we did not manage to analyze the effects of the lesion of one anterolateral quadrant alone, since cuts always encroached upon the lateral columns, lesion of this latter part of the spinal white matter alone did not modify the neuronal responses. In addition, the data obtained here establish that the pathway for noxious messages toward the VB neurons is completely crossed. These results demonstrate that various ascending pathways which are believed to be involved in some aspects of pain transmission are not involved in eliciting neuronal responses to noxious stimuli in the ventrobasal complex of the rat thalamus. This relates in particular to the spino-cervico-thalamic tract, the postsynaptic fibers of the dorsal column and the multi-synaptic pathway of Lissauer's tract since lesions of the dorsal or dorsolateral parts of the cord alone where they travel (see refs. 2 and 32) did not modify the receptive fields of noxious responsive VB neurons. The medial portion of the spinothalamic tract does not seem to be involved in this transmission either since lesions of the anterior part of the cord (Fig. 2) where its fibers course did not affect the neuronal responses. This result is in keeping with the demonstration li that the spinothalamic axons travel-
82 ing in the anterior portion of the cord project mostly, if not exclusively, onto intralaminar and/or medial thalamic nuclei. The possibility of an involvement of the spino-reticular systems in this transmission cannot be completely excluded from our data since this pathway travels in the anterolateral quadrant of the spinal cord 2°,28,35. Such a participation is, however, difficult to reconcile with the present electrophysiological findings. Indeed the spino-reticular projections, although largely crossed in the rat, have a direct component 4 and the spinal neurons from which they originate often respond to stimuli applied bilaterally on the body z3 (see also ref. 7 for results obtained from cats) whereas lesions of one anterolateral quadrant eliminated systematically in our study the responses to stimuli applied to contralateral receptive fields. Although one conclusion to be drawn from this study is the fact that the different pathways described above are not necessary for the transmission of noxious messages from the cord to the VB, it is not possible, in the absence of more precise and quantitative data, to preclude any role of these pathways in some aspects of this transmission. Our results indicate, however, that this role cannot be of major importance. In contrast, the present data suggest strongly that the lateral spino-thalamic tract, which projects directly onto the lateral thalamus, and in particular the ventrobasal complex, is necessary for neuronal responses to noxious stimuli in the VB. Indeed, these fibers travel in the anterolateral quadrant of the spinal cord n and, in the rat, this pathway is completely crossed 9,t9,20,27.35. This result is similar to that obtained by Poggio and Mountcastle 29 regarding the spinal pathways necessary for neuronal responses to noxious stimuli in the PO of the cat. A recent report of bilaterally projecting spinothalamic neurons in the rat~5 could be at variance to this interpretation. It is however difficult to determine the actual significance of these results for our study since the authors observe less than 2% of spinothalamic neurons which project bilaterally (and even much less when considering the lumbar cord which is the area of interest for the present study); in addition, the injection sites they show are particularly large and certainly involve at least a part of the intralaminar nuclei since in all cases of 'lateral thalamus injections', retrogradely la-
beled neurons are observed in the pontomedullary reticular formation which, for the authors themselves, 'was considered indicative of successful injections into the intralaminar complex'. Considering the wealth of data showing that lateral STT originating from the lumbar cord is crossed in the rat".~'.:°,.'-7. ~, the following discussion cannot take into account the possible existence of a minute population of bilaterally projecting lateral spinothalamic neurons proposed by Kevetter and Willis 15. This conclusion leads us back, however, to the problem posed at the beginning of this paper: the neuronal responses to noxious stimulation in the VB cannot be reconciled directly with the anatomical data on the organization of the spino-thalamic projections. In addition, although numerous common characteristics are found, several differences can be observed between the responses to somatic stimuli recorded in the dorsal horn of the spinal cordZi,2:. particularly from spinothalamic neurone .~,,s and those of VB neurons13, 24. In particular, m the rat, many VB neurons are exclusively excited by noxious stimuli, while many spinothalamic neurons are 'convergent' and also VB neurons have large and often bilateral receptive fields unlike the dorsal horn cells. The present results, taken together with recent data, indicate a clue to the basis for these paradoxical data. Indeed, the spinal dorsal horn neurons at the origin of the lateral spino-thalamic tract in the rat 6,8,9-11 have unilateral receptive fields and the spino-thalamic projection is completely crossed: this suggests that the only information which arrives directly in the VB from this pathway will be from the contralateral half of the body. tn these circumstances, information conveyed by the lateral spinothalamic tract from the ipsilateral half of the body, must arrive from the opposite VB. Since there is no evidence for direct projections from one VB to the other and as all VB neurons, in the rat. project towards the somatosensory (SI) cortex ls.?~, the information would seem to have to be conveyed through the cortex. The present demonstration that neuronal responses to noxious stimuli in the VB are related to messages conveyed in the lateral spinothalamic pathway thus strongly supports the hypothesis that these responses are, at least partly, dependent upon a thalamo-cortical loop. This explanation could also apply to the existence of large contratateral receptivc
83 fields, since in the VB, spinothalamic p r o j e c t i o n s are strictly somatotopically organized 27 and there are no
sal horn and what is r e c o r d e d in the VB could take place at the cortical level. On the basis of this specu-
local circuit neurons or axonal collaterals of VB neurons 18,26 which could have been a possible basis for the convergence of h e t e r o t o p i c messages onto one particular neuron. Messages concerning two different limbs, for instance, would be first t r a n s m i t t e d to two different sets of VB neurons which, themselves, project directly toward the SI cortex without giving off collaterals within the VB nucleus. Recent electrophysiological studies of S1 cortical neurons responsive to noxious stimuli are in keeping with this hypothesis. I n d e e d , it has been shown that most noxious responsive SI neurons which are principally located in layer V of the cortex and thus might
lation, some noxious responsive neurons in the thalamic ventrobasal complex would thus r e s p o n d both to spino-thalamic inputs and to spino-thalamo-cortico-thalamic inputs. The small n u m b e r of 'convergent' neurons in the VB, which present some 'spinallike' characteristics 13 could subserve a role as relaycells for this loop. The present results showing that the responses to non-noxious stimuli of two of these 'convergent' neurons studied here do not d e p e n d upon the integrity of the dorsal column system suggest, as would be required by this scheme, that they directly receive spino-thalamic inputs. Which SI cortical neurons receive the recurring noxious messages originating from the VB neurons at the end of the loop is a point that remains to be e l a b o r a t e d . Electrophysiological experiments involving t e m p o r a r y inactivation of thalamic and cortical structures are presently in progress to define m o r e precisely the neural circuitry of this hypothesized thalamo-cortico-thalamic loop.
receive direct thalamo-cortical projections (see refs. and discussion in ref. 31) present electrophysiological characteristics closer to those o b s e r v e d in the spinal cord than to those of VB neurons in that they have 'convergent' p r o p e r t i e s and relatively small contralateral receptive fieldsl6,17. This paradoxical result has to be i n t e r p r e t e d in the light of the fact that, in contrast, cortical neurons specifically excited by noxious stimuli applied to large receptive fields, i.e. 'VB-like' neurons, are located mostly in layer VI, where most cortico-thalamic neurons are located 14,33.34. In this scheme, some cortical neurons presenting response characteristics similar to those recorded in the VB would thus a p p e a r in the loop before~ and not after the VB neurons. This would suggest that part of the transformation of the noxious message between what is r e c o r d e d in the spinal dor-
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10 Giesler, G. J., Nahin, R. L. and Madsen, A. M., Postsyn-
84 aptic dorsal column pathway of the rat. I. Anatomical studies, J. Neurophysiol.. 51 (1984)260-275. 11 Giesler, G. J., Spiel, H. R. and Willis, W, D., Organization of spinothalamic tract axons within the rat spinal cord, J. comp. Neurol., 195 (1981) 243-252. t2 Giesler, G. J,, Urca, G., Cannon, J. T. and Liebeskind, J. C., Response properties of neurons of the lateral cervical nucleus in the rat, J. comp. Neurol., 186 (1979) 65-78. 13 Guilbaud, G., Peschanski, M,, Gautron, M. and Binder, D., Neurones responding to noxious stimulation in VB complex and caudal adjacent regions in the thalamus of the rat, Pain. 8 (1980) 303-318. 14 Jacobson, S, J. and Trojanowski, J. Q,, Corticothalamic neurons and thalamocortical terminal fields: an investigation in rat using horseradish peroxidase and autoradiography, Brain Research, 85 (1975) 385-40l. 15 Kevetter. G. A. and Willis, W. D., Collaterals of spinothalamic cells in the rat, J. comp. Neurol., 215 (1983) 453-464. 16 Lamour, Y., Guilbaud, G. and Wilier, J. C., Rat somatosensory (SI) cortex. I. Characteristics of neuronal responses to noxious stimulation and comparison with responses to non-noxious stimulation, Exp. Brain Res., 49 (1983) 39-45. 17 Lamour, Y., Guilbaud, G. and Wilier, J. C., Rat somatosensory (SI) cortex. II. Laminar and columnar organization of noxious and non-noxious inputs, Exp. Brain Res'., 49 (1983) 46-54. 18 Lee, C. L., The Structural Organization of the Rat Ventrobasal Thalamic Complex, Ph, D. Thesis. University of California, Berkelv, 1981. 19 Lund, R. D. and Webster, K. E., Thalamic afferents from the spinal cord and trigeminal nuclei. An experimental anatomical study in the rat. J. comp, Neurol.. 130 (1967) 313-324. 20 Mehler, W. R., Some anatomical species differences. A posteriori, Ann. N. Y. Acad. Sci., 167 (1969) 424-468. 21 M~n~trey, D., Giesler, G. J. and Besson. J, M., An anal),sis of response properties of spinal cord dorsal horn neurones to non-noxious and noxious stimuli in the rat, Exp. Brain Res., 27 (1977) 15-33. 22 M6n~trey, D., Chaouch, A. and Besson, J. M., Responses of spinal cord dorsal horn neurones to non-noxious and noxious cutaneous temperature changes in the spinal rat, Pain. 6 (1979) 265-282, 23 M~n6trey, D., Chaouch, A. and Besson, J, M., Location and properties of dorsal horn neurons at the origin ol' the spinoreticular tract in the lumbar enlargement of the rat, J, Neurophysiol.. 44 (1980) 862-877.
24 Peschanski, M., Guilbaud, G., Gautron, M. anti Bcsson, J. M,, Encoding of noxious heat messages m neurons of the ventrobasal thalamic complex of the rat, Brain Research, 197 (1980) 401-413. 25 Peschanksi, M., Guilbaud, G,, Lce, C. L, and Mantyh, P. W., Involvement of the rat ventrobasaI thalamic complex in the sensory-discriminative aspects of pain: electrophysiological and anatomical data. In G. Macchi, A. Rustioni and R. Spreafico (Eds.), Somatosensory Integrauon m the Thalamus, Elsevier, Amsterdam, 1983, p p 147 --163. 26 Peschanski, M., Lee, C. l~. and Ralston, H. J. Ill, The structural organization of the ventrobasal complex o1 the rat as revealed by the analysis of physiologically characterized neurons injected intracellularly with horseradish peroxidase, Brain Research, 297 (1984) 63-74. 27 Peschanski, M., Mantyh, P. W. and Besson, J. M., Spinal afferents to the ventrobasal thalamic complex m the rat: an anatomical study using wheabgerm agglutinin conjugated to horseradish peroxidase, Brain Research, 278 (1983) .~40-~44. 28 Petrovicky, P., Distribution and organization ol spino-reticular afferents in the brainstem of the rat, Z. Hirnforsch., 17(1976) 127-135. 29 Poggio, G. F. and Mountcastlc, V. B., Stud), of the functional contributions of the lemniscat and sPin0thalamic systems to somatic sensibility, Bull. Johns Hopk. ttosp., 106 (1960) 266-316. 30 Saporta, S. and Kruger, k., The organization of thalamocortical relay neurons in the rat ventrobasal complex studied by the retrograde transport of horseradish peroxidase, J. comp. Neurol.. 174 (1977) 187-208. 31 White, E. L., Thalamocortical synaptic relations: a review with emphasis on the projections of specific thalamic nuclei to the primary sensory areas of the neocortex, Brain Res, Rev., 1 (1979)275-31l. 32 Willis, W. D. and Coggeshall. R~ E., Sensory Mechanisms of the Spinal Cord, Plenum, 1978, New York. 33 Wise, S, P.. The laminar organization of certain afferent and efferent fiber systems in the rat somatosensory cortex. Brain Research, 90 (1975) 139-142. 34 Wise, S. P, and Jones, E. G., Cells of origin and terminal distribution of descending projections of the rat somatosensory cortex, J. comp. Neurol., 175 (1977) 129-158. 35 Zenflan, F. P.. Leonard, C. M,, Kow, L. M, and Pfaff, D. W., Ascending tracts of the lateral column of the rat spinal cord: a study using the silver impregnation and horseradish peroxidase techniques, Exp. Neurot., 62 (1978) 298334.
77
BRE 10958
Electrophysiological Evidence for a Role of the Anterolateral Quadrant of the Spinal Cord in the Transmission of Noxious Messages to the Thalamic Ventrobasal Complex in the Rat MARC PESCHANSKI, ANNIE BRIAND, MICHI~LE GAUTRON and GISE,LE GUILBAUD Unit( de Recherches de Neurophysiologie Pharmacologique, U 161 INSERM, Paris 75014 (France)
(Accepted December 4th, 1984) Key words'." nociception - - thalamic VB neurons - - spinal pathways - - anterolateral quadrant
Responses to noxious mechanical and thermal stimulation applied to the hindpaws were recorded extracellularly from the same neurons of the ventrobasal complex of the rat thalamus (VB) before and after lesions of various areas of the cervical cord in order to determine the pathways carrying the afferent messages. It was demonstrated that lesions of the dorsal and dorsolateral portions of the cord failed to eliminate the VB neuronal responses to noxious stimulation. By contrast, lesion of one anterolateral quadrant eliminated the responses to a noxious stimulation applied to the hindpaw contralateral to the lesion. This occurred whether the lesion was ipsilateral or contralateral to the recording site. From the present study and the data in the literature, it is concluded that the fibers of the spino-thalamic tract which are completely crossed in the spinal cord, travel in the anterolateral quadrant and project directly onto the VB, are involved in the transmission of noxious messages from the cord to the VB neurons. This conclusion indicates that the VB neuronal responses to noxious stimulation of the hindpaw ipsilateral to the recording site depend on the spinothalamic projection to the opposite ventrobasal complex. This therefore suggests that some noxious messages which reach a particular VB neuron are conveyed via the opposite VB and the existence of a thalamo-cortico-thalamic loop is discussed.
INTRODUCTION
presence of terminals of the spinothalamic tract in this area 19,2o,27,35. However, it is difficult to reconcile
In their classical study, Poggio and Mountcastle 29
the anatomical data showing that the spinal projec-
demonstrated the presence of n e u r o n s activated by noxious stimulation in the posterior nuclear group (PO) of the cat thalamus, and claimed that these responses were associated with the existence of spino-
tions are strictly crossed and somatotopically organized in the VB with the characteristics of the receptive fields of VB noxious responsive neurons which are often large and symmetrically bilateral, with only
thalamic projections to this nucleus. F u r t h e r anatomical studies showing that spinal afferents could be demonstrated in this area in the cat ~,3 but not in the adjacent ventroposterior nucleus supported this hypothesis, underlining the possible role of the fiber paths in the anterolateral quadrant of the spinal cord in the transmission of noxious messages towards su-
a poor somatotopic organization (see discussion in ref. 25). This paradox led us to suggest that 'noxious inputs relayed by other pathway(s) than the spinothalamic tract had to be hypothesized '25. Amongst the pathways conveying noxious messages and originating from the spinal cord, 3 other ascending pathways could be considered (see references in refs, 2, 32): the spino-reticular system, the spino-cervico-thalamic path and the postsynaptic dorsal column system. The present experiment was therefore designed to determine whether the participation of one or more of these other pathways could explain some of the results obtained at the VB level.
praspinal structures. In the ventrobasal complex (VB) of the rat thalamus, we have observed n e u r o n s responding to noxious stimuli intermingled with n e u r o n s responding exclusively to non-noxious stimuli 13. This result again corresponds to the anatomical demonstration of the
Correspondence: M. Peschanski, Unit6 de Recherches de Neurophysiologie, U 161 INSERM, 2 rue d'Aldsia, Paris 75014, France.
0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
7~ The present study is based upon the extracellular recording of responses of the same VB neurons before and after successive restricted lesions of the spinal cord. The results of these experiments were analyzed taking into account the experimental data establishing that in the rat, the spinothalamic afferents to the lateral thalamus are strictly crossed 27 and travel in the anterolateral quadrant11 while the spino-reticular pathways travel in the same area but are both crossed and direct 4. By contrast, the two main remaining systems (spino-cervical tract and postsynaptic fibers of the dorsal columns) are uncrossed and ascend, respectively, in the dorsolateral and dorsal portions of the cord10,12. MATERIALS AND METHODS 24 Male Sprague-Dawley albino rats weighing between 240 and 300 g were anesthetized with a gaseous mixture of fluothane in nitrous oxide (2/3) and oxygene (1/3), paralyzed with an i.v. injection of gallamine triethiodide and artificially ventilated using a Palmer pump. The surgical preparation was made under deep anaesthesia using fluothane at a concentration of 3% which was then lowered to 0.5-0.6% and maintained at this level during the recording period. The level of anaesthesia was systematically checked by an electrocorticogram recorded longitudinally between two silver ball electrodes applied on the dura mater at the level of the frontal and occipital cortex. Under these conditions, the ECoG consisted of theta monomorphic waves of 4-5 Hz, 100-120 ~V associated with a few spindles of 1214 Hz. It was checked at the beginning of the experiments that noxious stimuli did not induce arousal reactions on the ECoG. The vascularization of the skin was checked by observing the colour of the extremities and their ability to return quickly to the previous state after application of pressure. The central temperature was maintained between 37 and 38 °C using a homeothermic blanket system.
Recording procedures A small craniotomy was made in the left part of the skull at the level of the VB as defined in previous experiments ~3, and the dura mater removed. The recording electrodes (10-15 Mff2) were glass micropipettes filled with a mixture of 5% NaC1 and ponta-
mine sky blue. The iontophoretic application of dye before the sacrifice and perfusion of the animal with formalin allowed the location of the recording site oil Nissl-stained sections of the VB. The VB neurons were characterized by their responses to mechanical stimulation, either non-noxious (brushing, strokes, pressure) or noxious (pinches) and to noxious thermal stimulation (plunging the paw in a 50 °C water bath) and their receptive fields were mapped. The interval between two successive noxious stimuli was 3 rain to limit the effects of sensitization and/or desensitization (see discussion in ref. 24). In the present study, 15 neurons were studied, responding to noxious stimulation either exclusively (n = 13) or, in two cases, with an additional response to non-noxious stimuli (convergent neurons). Their receptive fields for noxious stimulation included both hindpaws. Four other VB neurons responding exclusively to non-noxious stimulation applied to a restricted receptive field contralateral to the recording site were used as controls for possible non-specific effects of the spinal sections on the responses of VB neurons.
Experimental protocol During the surgical procedure, the skin and muscles overlying the cervical vertebrae were cut and access to the cord gained by two or three laminectomies usually including vertebrae C3. C5 and C7. The spinal cord was left exposed but covered with saline. Once a neuron had been characterized by repetitive noxious and non-noxious mechanical and noxious thermal stimuli applied to both hindpaws, a lesion of a portion of the spinal cord was performed using either a small sharp knife or a lancet diamond knife (A. Meyer Co.). It was checked that slitting the dura mater overlying the spinal cord did not modify the size or the shape of the spikes. In some of the noxious neurons, opening the dura was accompanied by a neuronal discharge which could be interp.reted as a response to a noxious stimulation since "control' neurons responsive only to non-noxious stimulation did not exhibit this reaction. We only analyzed the neuronal responses at least 10 rain after the lesion had been performed to avoid the interference of possible non-specific reactions related to vegetative phenomena. It can be noted, however, that neither tachycardin nor changes of the ECoG recording were ob-
79 served. Responses of the neuron to the different stimuli applied r e p e a t e d l y on both hindpaws were analyzed at least during 30 min following the lesion. A second and in some cases a third lesion of the spinal cord could be p e r f o r m e d following the same protocol to study the responses of the same neuron after successive cutting of different spinal pathways. In these cases of multiple lesioning, each lesion was made at a different spinal level in o r d e r to allow clear interpretation of the histological data concerning their extent and location in the cord. The histological analysis was m a d e on 100-/~m thick sections cut serially on a freezing m i c r o t o m e and Nissl-stained with cresyl violet. The complete extent of each lesion was d e t e r m i n e d by superimposing
using a camera lucida, the drawings of the serial sections containing parts of the lesion. As can be seen in Fig. 1, it was possible to obtain relatively selective lesions of the dorsal columns (Fig. 1A) or of the dorsolateral funiculus on one side (Fig. 1B). Lesions of the anterolateral quadrant often encroached upon the lateral column and, due to the difficulty of maintaining a stable recording during the spinal lesions, it was not possible, in our experimental conditions, to perform a selective lesion of the anterolateral quadrant (Fig. 1C). Finally, complete hemisections (Fig. 1D) could be produced. No strict protocol was followed with regard to the o r d e r of the lesions in o r d e r to avoid bias.
D
Fig. 1. Photomicrographs of 4 different examples of spinal lesions performed during the study. A: lesion of the dorsal columns. B: Icsion of the dorsolateral funiculus. C: lateral lesion involving mostly the anterolateral quadrant. D: hemisection. The sections presented here are those including the largest lesion in each case, but reconstruction of the complete lesions using the camera lucida extcnded them a little, although these are representative examples of the series.
Left Paw
RESULTS
~,,
Right Paw
All sites of i o n t o p h o r e t i c applications of p o n t a mine sky blue w e r e r e c o v e r e d and c o n f i r m e d that all the units r e c o r d e d w e r e located in the rostral p o r t i o n of the lateral VB. As d e s c r i b e d in a p r e v i o u s study ~3, no t o p o g r a p h i c a l s e g r e g a t i o n of n o x i o u s vs n o n - n o x ious r e s p o n s i v e or ' c o n v e r g e n t '
neurons
was ob-
served.
fl 50
Pinch
~//A\~////~
In all 4 ' c o n t r o l ' n o n - n o x i o u s r e s p o n s i v e n e u r o n s ,
I
50
Pinch
the r e s p o n s e s to p e r i p h e r a l s t i m u l a t i o n of the r e c e p tive field w e r e not r e d u c e d as long as the dorsal col-
lOHz t
u m n p a t h w a y c o n t r a l a t e r a l to the r e c o r d i n g site was intact, e v e n w h e n m o s t o t h e r areas of the c o r d w e r e d e s t r o y e d by successive cuts. This finding d e m o n strates that the p r o c e d u r e we used allows the spinal p a t h w a y for a p a r t i c u l a r type of m e s s a g e to be d e t e r m i n e d w i t h o u t any o b v i o u s non-specific effects of spinal section. T h e results o b t a i n e d f r o m the 15 n e u r o n s r e s p o n sive to n o x i o u s s t i m u l a t i o n strongly suggest the inv o l v e m e n t of the a n t e r o l a t e r a l q u a d r a n t of the c o r d in the t r a n s m i s s i o n of n o x i o u s inputs t o w a r d t h e V B . In 7 cases (5 n o x i o u s n e u r o n s and the 2 ' c o n v e r g e n t '
I 5O
tl
;
it
50
Pinch
tl
Pinch
Fig. 3. Series of peristimulus histograms showing the effects of a spinal hemisection performed on the same side as the recording site as indicated in the scheme. Responses to a pinch of the hindpaws (arrows) and a noxious thermal stimulus (50 °C water bath) are indicated on the top trace for the controls, on the left side for the left paw, on the right side for the right paw, Bottom trace shows the responses of the same VB neuron to the same noxious stimuli 10-30 min after the section.
n e u r o n s ) , it was n o t possible to e l i m i n a t e the activation of the n e u r o n s by s t i m u l a t i o n of e i t h e r h i n d p a w despite large cuts in the spinal cord. It was f o u n d , during histological c o n t r o l s , ~hat t h e s e cuts n e v e r inv o l v e d a c o m p l e t e half of the spinal cord, always leaving u n t o u c h e d at least the a n t e r o l a t e r a l q u a d r a n t
right hindpaw 50oc
(Fig. 2). Lesions of the dorsal cord, d o r s o l a t e r a l fu-
L
a
i
b
c~d
~2
t~
c
d
Fig. 2. a-e: camera lucida drawings showing the lesions reconstructed from serial 100/~m Nissl-stained sections in cases where no clear effect of spinal lesions of the VB neuronal responses to noxious stimulation could be observed. In e, the scheme shows a composite superimposition of the various examples, to show the total extent of spinal lesions which did not modify the receptive fields of the VB noxious responsive neurons.
5Hz Fig. 4. Series of peristimulus histograms showing the effects ol successive lesions of the dorsal ( l 2), dorsolateral (3) and lateral (4) cervical cord (respectively at C5. C3 and C7) on the rcsponse of the same VB neuron to noxious pinch of the hindpaw contralateral to the 1ast lesion (lateral).
81 niculus, lateral column or anteromedial tract were ineffective in modifying the receptive fields of the noxious responsive VB neurons. It can be underlined that this result applies also to the responses to nonnoxious stimulation in the two 'convergent' neurons which did not disappear after lesions destroying most of the dorsal part of the cord. Results obtained in the 8 other neurons exclusively activated by noxious stimulation were similar whatever the order of the lesions. Figs. 3, 4 and 5 are representative examples of these results obtained using either mechanical or thermal noxious stimuli. Cuts in any part of the dorsal cord, i.e. dorsal columns, Lissauer's tract or dorsolateral funiculus failed to eliminate the neuronal responses to noxious stimuli applied to either hindpaw (Fig. 4). A further lesion of one anterolateral quadrant of the cord eliminated completely the response of the neuron to noxious stimuli applied to the hindpaw contralateral to the lesion site. In complete contrast, the neuronal responses elicited by noxious stimulation applied to the hindpaw contralateral to the unlesioned anterolateral quadrant was preserved, whether this part of the receptive field was contralateral (Fig. 3) or ipsilateral (Fig. 5) to the recording site. The elimination of a part of the receptive field of a particular neuron was most often the only clear alteration of its response following multiple lesions, and this was observed as
Left Paw
Right Paw
I
{
II
tl
)'
t l
'1(
t l
Fig. 5. Series of peristimulus histograms showing the effects of a spinal hemisection performed on the side contralateral to the recording site. Legend as in Fig. 2.
long as the recording of the neuronal activity was continued, which could be more than 60 min after the lesion in most cases. In 5 other cases, not considered above, the neurons which had been tested before the lesion of the cord were lost during or just after hemisection of the cord ipsilateral to the recording site. In these cases, other noxious responsive neurons were recorded after the lesion, exhibiting a completely unusual feature in that they responded to noxious stimuli applied to the hindpaw ipsilateral to the recording site but not to that contralateral to it while receptive fields of VB noxious neurons are, in normal rats, either contralateral or bilateral but not ipsilateral to the recording sitel3. DISCUSSION The present electrophysiological study demonstrates that, in the rat, neuronal responses to noxious stimuli recorded in the thalamic ventrobasal complex depend upon the integrity of, at least, an anterolateral quadrant of the spinal cord. Indeed, although we did not manage to analyze the effects of the lesion of one anterolateral quadrant alone, since cuts always encroached upon the lateral columns, lesion of this latter part of the spinal white matter alone did not modify the neuronal responses. In addition, the data obtained here establish that the pathway for noxious messages toward the VB neurons is completely crossed. These results demonstrate that various ascending pathways which are believed to be involved in some aspects of pain transmission are not involved in eliciting neuronal responses to noxious stimuli in the ventrobasal complex of the rat thalamus. This relates in particular to the spino-cervico-thalamic tract, the postsynaptic fibers of the dorsal column and the multi-synaptic pathway of Lissauer's tract since lesions of the dorsal or dorsolateral parts of the cord alone where they travel (see refs. 2 and 32) did not modify the receptive fields of noxious responsive VB neurons. The medial portion of the spinothalamic tract does not seem to be involved in this transmission either since lesions of the anterior part of the cord (Fig. 2) where its fibers course did not affect the neuronal responses. This result is in keeping with the demonstration li that the spinothalamic axons travel-
82 ing in the anterior portion of the cord project mostly, if not exclusively, onto intralaminar and/or medial thalamic nuclei. The possibility of an involvement of the spino-reticular systems in this transmission cannot be completely excluded from our data since this pathway travels in the anterolateral quadrant of the spinal cord 2°,28,35. Such a participation is, however, difficult to reconcile with the present electrophysiological findings. Indeed the spino-reticular projections, although largely crossed in the rat, have a direct component 4 and the spinal neurons from which they originate often respond to stimuli applied bilaterally on the body z3 (see also ref. 7 for results obtained from cats) whereas lesions of one anterolateral quadrant eliminated systematically in our study the responses to stimuli applied to contralateral receptive fields. Although one conclusion to be drawn from this study is the fact that the different pathways described above are not necessary for the transmission of noxious messages from the cord to the VB, it is not possible, in the absence of more precise and quantitative data, to preclude any role of these pathways in some aspects of this transmission. Our results indicate, however, that this role cannot be of major importance. In contrast, the present data suggest strongly that the lateral spino-thalamic tract, which projects directly onto the lateral thalamus, and in particular the ventrobasal complex, is necessary for neuronal responses to noxious stimuli in the VB. Indeed, these fibers travel in the anterolateral quadrant of the spinal cord n and, in the rat, this pathway is completely crossed 9,t9,20,27.35. This result is similar to that obtained by Poggio and Mountcastle 29 regarding the spinal pathways necessary for neuronal responses to noxious stimuli in the PO of the cat. A recent report of bilaterally projecting spinothalamic neurons in the rat~5 could be at variance to this interpretation. It is however difficult to determine the actual significance of these results for our study since the authors observe less than 2% of spinothalamic neurons which project bilaterally (and even much less when considering the lumbar cord which is the area of interest for the present study); in addition, the injection sites they show are particularly large and certainly involve at least a part of the intralaminar nuclei since in all cases of 'lateral thalamus injections', retrogradely la-
beled neurons are observed in the pontomedullary reticular formation which, for the authors themselves, 'was considered indicative of successful injections into the intralaminar complex'. Considering the wealth of data showing that lateral STT originating from the lumbar cord is crossed in the rat".~'.:°,.'-7. ~, the following discussion cannot take into account the possible existence of a minute population of bilaterally projecting lateral spinothalamic neurons proposed by Kevetter and Willis 15. This conclusion leads us back, however, to the problem posed at the beginning of this paper: the neuronal responses to noxious stimulation in the VB cannot be reconciled directly with the anatomical data on the organization of the spino-thalamic projections. In addition, although numerous common characteristics are found, several differences can be observed between the responses to somatic stimuli recorded in the dorsal horn of the spinal cordZi,2:. particularly from spinothalamic neurone .~,,s and those of VB neurons13, 24. In particular, m the rat, many VB neurons are exclusively excited by noxious stimuli, while many spinothalamic neurons are 'convergent' and also VB neurons have large and often bilateral receptive fields unlike the dorsal horn cells. The present results, taken together with recent data, indicate a clue to the basis for these paradoxical data. Indeed, the spinal dorsal horn neurons at the origin of the lateral spino-thalamic tract in the rat 6,8,9-11 have unilateral receptive fields and the spino-thalamic projection is completely crossed: this suggests that the only information which arrives directly in the VB from this pathway will be from the contralateral half of the body. tn these circumstances, information conveyed by the lateral spinothalamic tract from the ipsilateral half of the body, must arrive from the opposite VB. Since there is no evidence for direct projections from one VB to the other and as all VB neurons, in the rat. project towards the somatosensory (SI) cortex ls.?~, the information would seem to have to be conveyed through the cortex. The present demonstration that neuronal responses to noxious stimuli in the VB are related to messages conveyed in the lateral spinothalamic pathway thus strongly supports the hypothesis that these responses are, at least partly, dependent upon a thalamo-cortical loop. This explanation could also apply to the existence of large contratateral receptivc
83 fields, since in the VB, spinothalamic p r o j e c t i o n s are strictly somatotopically organized 27 and there are no
sal horn and what is r e c o r d e d in the VB could take place at the cortical level. On the basis of this specu-
local circuit neurons or axonal collaterals of VB neurons 18,26 which could have been a possible basis for the convergence of h e t e r o t o p i c messages onto one particular neuron. Messages concerning two different limbs, for instance, would be first t r a n s m i t t e d to two different sets of VB neurons which, themselves, project directly toward the SI cortex without giving off collaterals within the VB nucleus. Recent electrophysiological studies of S1 cortical neurons responsive to noxious stimuli are in keeping with this hypothesis. I n d e e d , it has been shown that most noxious responsive SI neurons which are principally located in layer V of the cortex and thus might
lation, some noxious responsive neurons in the thalamic ventrobasal complex would thus r e s p o n d both to spino-thalamic inputs and to spino-thalamo-cortico-thalamic inputs. The small n u m b e r of 'convergent' neurons in the VB, which present some 'spinallike' characteristics 13 could subserve a role as relaycells for this loop. The present results showing that the responses to non-noxious stimuli of two of these 'convergent' neurons studied here do not d e p e n d upon the integrity of the dorsal column system suggest, as would be required by this scheme, that they directly receive spino-thalamic inputs. Which SI cortical neurons receive the recurring noxious messages originating from the VB neurons at the end of the loop is a point that remains to be e l a b o r a t e d . Electrophysiological experiments involving t e m p o r a r y inactivation of thalamic and cortical structures are presently in progress to define m o r e precisely the neural circuitry of this hypothesized thalamo-cortico-thalamic loop.
receive direct thalamo-cortical projections (see refs. and discussion in ref. 31) present electrophysiological characteristics closer to those o b s e r v e d in the spinal cord than to those of VB neurons in that they have 'convergent' p r o p e r t i e s and relatively small contralateral receptive fieldsl6,17. This paradoxical result has to be i n t e r p r e t e d in the light of the fact that, in contrast, cortical neurons specifically excited by noxious stimuli applied to large receptive fields, i.e. 'VB-like' neurons, are located mostly in layer VI, where most cortico-thalamic neurons are located 14,33.34. In this scheme, some cortical neurons presenting response characteristics similar to those recorded in the VB would thus a p p e a r in the loop before~ and not after the VB neurons. This would suggest that part of the transformation of the noxious message between what is r e c o r d e d in the spinal dor-
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ACKNOWLEDGEMENTS The authors are greatly i n d e b t e d to Dr. J, M. Besson for his help with the manuscript, to E. Dehausse and J. Carrou6 for their technical assistance and to Dr. A, H. Dickenson for his review of the English. A. Briand is assistante of the Facult6 de M6decine de Caen. S u p p o r t e d by I N S E R M .
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