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Oral nociceptive activity in the rat superior colliculus
275
Brain Research, 549 (1991) 275-284 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 ADONIS 000689939116617X BRES 16617
Oral nociceptive activity in the rat superior colliculus P. Auroy, B. Irthum and A. Woda Laboratoire de Physiologie Orofaciale, Facultd de Chirurgie Dentaire, Clermont Ferrand (France) (Accepted 11 December 1990) Key words: Nociception; Orofacial receptive field; Superior colliculus, Rat
Single units were recorded using extracellular glass microelectrodes in all laminae of the superior colliculus of the rat under haiothane nitrous oxide anaesthesia. Fifty-one units were encountered which responded to a low intensity mechanical stimulus applied to a contralaterai or bilateral field located in the oral sphere (intraoral 11, perioral 16), on the face (29) or on the rest of the body (21). Sixteen units responded to a jaw movement. Sixty-one cells were recorded which were preferentially (10) or only (51) activated (30) or inhibited (21) by noxious stimuli. Contralateral or bilateral mechanoreceptive fields located in intraoral (34) and perioral (35) areas were frequent. There is therefore a high incidence of the nociceptive representation of the mouth in the superior colliculus. The other functional properties of the nociceptive units were similar to those reported in other studies. From the subsequent histological localization of the recorded units, it appeared that the nociceptive projections from the intraoral and perioral regions to the superior colliculus reach the lateral part of the intermediate and deep layers of the superior colliculus.
INTRODUCTION The architecture of the superior colliculus (SC) in the rat is characterized by a laminar organization with alternating layers of white and grey matter. The upper layers are involved in vision whereas the intermediate and deep layers are multimodal with somesthesia predominating. M a n y anatomical studies have established that the trigeminal sensory complex (TSC) projects heavily into the superior colliculus. In particular, the subnuclei interpolaris and oralis project into the rostral two thirds of the intermediate and deep layers of the contralateral SC in the cat 26 as well as in different rodents 2'7'8"39"4°'44. U n i t recordings in the deep layers of the SC have also confirmed the existence of a representation of trigeminal somesthesia and especially of the face and vibrissae 1°'24'31,33,52,65,68,71. Moreover, stimulation of the mesencephalic projections of the spinotectal tract produces pain in m a n and behaviours indicative of pain in the cat 51'64. Microelectrode studies in the hamster 36" 46,61,66 and in the rat 49 have shown that the SC contains n e u r o n s which respond preferentially, or only, to nociceptive stimuli. Because of these facts and also because of the large representation of the mouth in the subnucleus oralis 4'16, the presence in the SC, of n e u r o n s activated by nociceptive stimulation of the intra- or perioral trigeminal field
can be postulated. Consequently, the aim of this study was to investigate the receptive fields and the functional characteristics of the collicular units responding to high intensity somesthesic stimulation.
MATERIALS AND METHODS Thirty-four male Sprague-Dawley rats weighing between 220 and 280 g were used for this experiment. These weight limits enabled us to use the stereotaxic coordinates given in the atlas of Albe-Fessard et al. 1. Anaesthesia All animals were anaesthetized initially with an intraperitoneal (i.p.) injection of Ketamine hydrochloride (120 mg/kg) in order for a tracheotomy to be carried out. Anaesthesia was maintained during surgery with a mixture of 1/3 02, 2/3 N20 and halothane at a concentration of 1.5%. This halothane concentration was then reduced and maintained at 0.5% during the recording periods. The animals were allowed to breathe spontaneously. The level of anaesthesia was systematically checked by an electro-corticogramme (EcoG) recorded longitudinally using two silver ball electrodes applied to the dura. Thus, all the units in this study were recorded during a stable and moderate state of anaesthesia, which was sufficient however to avoid clinical or electrocortical signs of suffering, i.e. arousal, caused by the application of noxious stimuli. The EcoG usually consisted of a 4-5 Hz theta rhythm associated with a few spindles. The vascularization of the peripheral cutaneous receptive fields was checked by observing the colour of the extremities and their ability to return quickly to their previous state after application of pressure. The central temperature was maintained at 37-38 °C with a homeothermic blanket system. The cardiac rhythm was continuously monitored.
Correspondence: A. Woda, Laboratoire de Physiologic Orofaciale, Facult6 de Chirurgie Dentaire, 11 Bd Charles de Gaulle, 63000 Clermont Ferrand, France.
276
Surgical preparation A craniectomy was carried out with a drill, exposing a 5 mm rostro-caudal extent of the dura mater directly above the position of the SC, -1 - + 4 mm according to the stereotaxic coordinates of Albe-Fessard et al.l, and laterally 4 mm from either side of the midline. The dura mater was incised and folded back onto the sides of the craniectomy and over the superior sagittal sinus which was thus protected. On the first 6 rats, an occipital lobectomy was performed by aspiration of the cerebral tissue revealing the surface of the SC. On the following 28 rats, the SC was reached by a transcortical electrode penetration.
with a binocular microscope. An iontophoretic injection (15/tA, 20 min) of a saline solution of Pontamine blue was performed at the end of each track. The resulting blue points permitted the localization of the collicular recording sites which were then plotted onto the corresponding maps of the stereotaxic atlas of AlbeFessard et al. 1 (frontal planes A 1.2-A 2.9).
Recordings Recordings were made using glass micropipettes of a resistance of 6-10 M~2, filled with a mixture of 5% NaCI and Pontamine sky blue. Penetration of the upper layers of the SC was guided by the presence of cells responding to visual stimuli. As the microelectrode was advanced deeper into the SC, visual, acoustic, noxious and non-noxious mechanical stimuli were systematically applied in search for evoked activity. If evoked or spontaneous activity of a single unit was clearly differentiated, then mechanical stimuli were further applied to all cutaneous and mucosal areas so as to characterize the unit. More detailed descriptions of the methodology used for stimulation and recording can be found elsewhere 15'
m e c h a n i c a l , acoustic o r visual stimuli w e r e r e c o r d e d .
RESULTS Two
16,55
The sensory stimuli included visual stimuli, such as the turning-on or switching-off a light and the movement of a light across the visual field, and also acoustic stimuli such as the clinking of metal objects, whistling or handclapping. Non-noxious mechanical stimuli included localized air puffs, brushing with a soft paint brush or rubbing with a blunt wooded probe. Noxious stimuli included heavy pressure, pinpricks or pinching with fine forceps (tip area 1 mm 2) which produced forces of 0.5-1.5 kg and provoked noxious sensations when applied to the experimenter's skin. The extent of the unit's receptive field was determined and drawn, and its location was designated in terms of its involvement in intraoral regions (lip, lingual, palatal or cheek mucosa, periodontium), perioral regions (hairy part of the lip, muzzle), facial regions or other parts of the body (see Fig. 7 in Dallel et a1.15). The units' responses to the mechanical stimuli allowed us to classify them into 4 groups. (1) Low threshold (LT) mechanoreceplive units which responded to hair movement, touch and light pressure applied to the skin surface. They showed no increase in discharge frequency with more intense stimuli and these were considered to be non-nociceptive tactile units. (2) Wide dynamic range (WDR) units which responded to low-intensity and highintensity cutaneous mechanical stimuli. They showed an increase in discharge frequency with more intense stimuli and were considered to be non-specific nociceptive units. (3) Units which were only activated by high-intensity mechanical stimuli (heavy pressure and/or pinch) and were considered to be nociceptive specific (Ns) units. (4) Units which exhibited a spontaneous activity that decreased or was suppressed following a high-intensity mechanical stimulation. They were called inhibitory nociceptive specific units (Ns inh). The differentiation of the recorded units into fibres and soma was made according to the criteria defined by Azerad et al. 3. Some units were analyzed 10 min after an injection of morphine (5 mg/kg i.p.), then 10 min after an injection of naloxone (0.5 mg/kg i.p.) in order to confirm their nociceptive character. The responses were recorded on an oscilloscope screen in the shape of a peristimulus time histogram and were photographed as previously described 15.
Location of the recorded units After sacrificing the animal, the brain was removed and placed in a fixative 10% formalin solution. The mesencephalon was then sliced into frontal serial sections of 100/~m which for 15 rats were stained using the Kluver-Barrera technique so as to show the laminated structure of the SC. The Nissi-staining method (Cresyl violet) was used for the other animals. The slices were examined
hundred
and
twenty-six
units
responding
to
Sixty-seven units w e r e a c t i v a t e d by low intensity m e c h a n ical stimuli (tactile) and 61 units w e r e a c t i v a t e d by high intensity m e c h a n i c a l stimuli ( n o c i c e p t i v e ) (Table I). A l t h o u g h this study was n o t d i r e c t l y c o n c e r n e d with the f u n c t i o n a l p r o p e r t i e s of the n o n - s o m e s t h e s i c units, we r e c o r d e d 91 units (89 s o m a and 2 fibres) which r e s p o n d e d to visual stimuli (Fig. 1A). F o u r t e e n units w e r e a c t i v a t e d by acoustic stimuli. F i v e units with a visual r e s p o n s e and 2 units with an a u d i t o r y r e s p o n s e w e r e also a c t i v a t e d by low intensity
(4 times)
or
high
intensity
(3 times)
m e c h a n i c a l stimulation. T h e l o c a t i o n of the r e c o r d i n g sites shows that the units r e s p o n d i n g to visual stimulation w e r e m a i n l y f o u n d in the u p p e r layers, w h e r e a s cells in the layers b e l o w w e r e p r e d o m i n a n t l y a c t i v a t e d by auditory and s o m a t o s e n s o r y
stimuli.
Units responding
to
a u d i t o r y stimuli w e r e f o u n d m a i n l y in t h e p o s t e r i o r and lateral parts,
w h e r e a s the units r e s p o n d i n g
to visual
stimuli w e r e l o c a t e d m o r e in t h e a n t e r i o r and m e d i a l parts.
Units activated by low intensity mechanical stimuli Sixty-seven units (62 s o m a and 5 fibres) r e s p o n d e d to light m e c h a n i c a l stimuli. F i f t y - o n e units w e r e a c t i v a t e d by stimulation of the oral m u c o s a , the skin surface, hairs and vibrissae, and 16 units r e s p o n d e d to the m o b i l i z a t i o n of the t e m p o r o - m a n d i b u l a r j o i n t ( T M J ) .
TABLE I
Distribution of the recorded SC units according to the topographical location of their receptivefield It must be noted that units having a receptive field involving more than one of the mentioned regions of the body, have been counted more than once. The number of recorded units is specifed in the first column.
Number ofcells 67 10 30 21
LT WDR Ns Nsinh
lntraoral
Perioral Facial Body Jaw movement
11 3 12 2
16 3 20 19
29 4 16 11
21 1 5 3
16 1 0 0
277
Fig. 1. Different examples of responses obtained from recordings of SC units. The spikes which are shown in A are displayed in the shape of a peristimulus time histogram in B-E; each dot represents one spike and each bin lasts 1.5 s. The onset and offset of the visual or low intensity mechanical stimulations are represented by the empty arrows. The onset and offset of the high intensity mechanical stimulations are shown by the white arrows. The recordings represented in A, B, C, D, E are typical of responses obtained from cells called visual (V), low threshold (LT) somatosensory, low and high threshold somatosensory (WDR), nociceptive specific (Ns) or nociceptive specific presenting an inhibitory response (Ns inh). The diagrams represent the peripheral fields and the location of the cells on a frontal section of the SC. Fig. 1E shows the response to the stimulation of the contralateral side of the tongue (1) and of the lower lip (2). G, central grey; R, red nucleus; MG, medial geniculate nucleus; In, intermediate grey and white layers of the SC; Dp, deep layers of the SC; 3, nucleus of the oculomotor nerve.
Cutaneo-mucosal units The mechanoreceptive fields were located 36 times in the half of the body contralateral to the recording electrode; 15 times were these fields bilateral with the response being predominantly contralateral. The mechanoreceptive fields were considered as oral, i.e. intra- and periora115, when located in the mouth, on the muzzle or on the hairy part of the lips. The receptive fields were situated in the intraoral region (11 times), in the perioral region (16 times), in the facial region (29 times, 13 times concerning exclusively the vibrissae), and on the rest of the body (21 times). The functional characteristics of these units were generally those of cells responding to low intensity mechanical stimulation such as a light touching of the hairs or vibrissae, but sometimes it was necessary to press the skin with a blunt wooden probe in order to obtain a response. The responses were not adaptable (Fig. 1B) or were of the o n - o f f type. Of the 4 neurons responding with an inhibition of their spontaneous activity, 2 had only an inhibitory mechanoreceptive field which was
contralateral and clearly defined and 2 had both an inhibitory field and a wider spread, less well-defined excitatory field. Four neurons having a facial receptive field including the vibrissae, were also activated by acoustic (2 units) or visual (2 units) stimuli.
Units responding to the jaw movement It is difficult to differentiate between the jaw movement responses and those activities evoked by an irritation when a neuron is displaced in relation to the electrode tip during the jaw movement. For this reason, the jaw movement responses were only considered when they satisfied the 3 following criteria: (1) there was a response to a slight jaw movement; (2) there was no change in amplitude of the action potentials during the jaw movement; and (3) it was impossible to produce a cell activity by any other pressure likely to produce a head movement. Ten neurons were activated by a single jaw movement, giving either an increase (6 units) or a decrease (4 units) in their spontaneous discharge frequency. Three neurons were activated by a jaw move-
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-1 Fig. 2. Location of the units activated by low intensity mechanical stimuli. Left: diagram showing the units on a frontal section of the SC, 2 mm anterior to the interaural plane. Right: diagram showing the units on a horizontal section of the SC. The locations of the receptive fields are indicated as following: O, oral; ~), oral and facial: A, facial; O, oral, facial, and anterior part of the body; ~, anterior part of the body; ii, posterior part of the body; l , all the body: *. jaw movement. m e n t in 2 opposite directions giving an increase or decrease in their discharge frequency. Two neurons were activated by jaw m o v e m e n t s in several directions producing the same change in neuronal activity. O n e neuron r e s p o n d e d to both a tactile stimulation of a contralateral oral field and to a jaw m o v e m e n t , and another r e s p o n d e d to nociceptive stimulation and to a jaw m o v e m e n t (see Fig. 4). These units were not sensitive to jaw positions but to jaw movements. O p e n i n g the mouth for example p r o d u c e d a regular and p r o l o n g e d discharge which varied with the a m p l i t u d e and speed of the movement. No a t t e m p t was m a d e to differentiate between the origins (muscular, articular etc.) of these proprioceptive responses.
O
F
n=25
n=10
OF
A
n=16
n=l
Location of low threshold somatosensory units The location of the recording site was only possible for 43 units (Fig. 2). Thirty of t h e m were found in the i n t e r m e d i a t e and deep layers of the SC. Seventeen out of 19 cells having oral and/or facial fields were located in the rostral part of the SC, 8 units with a somatic field which excluded the oral sphere or the face were o b s e r v e d in the caudal part, but a significant n u m b e r (7) were also observed in a m o r e rostral location. Neurons activated by a jaw m o v e m e n t were observed scattered in the rostrocaudal direction.
Units activated by high intensity mechanical stimuli Sixty-one units (54 s o m a and 7 fibres, 10 W D R , 30 Ns and 21 Ns inh) r e s p o n d e d to intense mechanical stimu-
OFA
n=3
OFAP
n=4
P
n=l
FAP
n= 1
Fig. 3. Receptive fields of the units activated by high intensity mechanical stimuli. The different locations of the receptive fields have been represented as following: O, oral; F, facial; A, anterior part of body; P, posterior part of body. The oral sphere is shown in black. The number of units belonging to each of these 4 groups is indicated (n).
279 The 10 W D R units had a spontaneous, irregular activity between 0 and 5 Hz (Fig. 1C) which would seem to be a characteristic of these W D R collicular units 66. They responded distinctly to a slight stimulation of a cutaneous or oral mucosal field, or of the periodontium (6 units), to m o v e m e n t of the vibrissae (one unit) or of the jaw (one unit). Intense mechanical stimulation provoked an increase in the response which sometimes continued after the stimulation had ceased 46. It consisted of an excitation in 9 cases (Fig. 1C) and of an inhibition in the one case of a neuron which displayed high level spontaneous activity. The 51 nociceptive-specific units were activated only by intense mechanical stimuli. Thirty units responded with an increase in their baseline activity. This response was composed of an emission of high frequency bursts of action potential and was followed in most cases by a post-discharge (Fig. 1D). Three units (1 oral, 2 orofacial) also responded to visual stimuli. Twenty-one nociceptivespecific units responded with an inhibition of their spontaneous activity which frequently went above 20 Hz.
lation. The receptive fields of these units were mainly located in the oral and facial regions (Fig. 3). A m o n g the 48 units which had an oral receptive field (Fig. 3), 17 (12 Ns, 3 W D R , and 2 Ns inh) had all or part of their receptive field inside the mouth. The receptive fields situated in the orofacial region were generally clearly defined, of small surface area and involved: 1 part only of the trigeminal territory (26 times), 2 parts of the trigeminal territory (18 times), and 3 parts of the trigeminal territory (10 times). More rarely a diffused field was observed (7 times), sometimes bilateral, showing zones of varying sensitivity. When covering a part or all of the rest of the body, they were generally large and were not clearly defined. The receptive fields were contralateral to the recording electrode (33 units), ipsilateral (2 units) or bilateral (26 units). In this last case, we sometimes saw (8 units) that there were more responses from the contralateral part of the field (Fig. 4A). Some were discontinuous and were made up of zones which, when stimulated, resulted sometimes in an activation of the unit and sometimes in an inhibition.
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(5 ,i'
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Fig. 4. Example of a WDR cell response. Left: the diagrams represent the location of the cell and the territory of its receptive field. Right: the recordings of this unit displayed as a peristimulus time histogram; the onset and offset of the nociceptive stimuli are shown by the white arrows; the beginning and end of the jaw movement are shown by the empty arrows. A: a peristimulus time histogram showing the responses before the injection. B: responses obtained 18 min after the morphine injection. C: responses obtained 10 min after the naloxone injection. 1, stimulation of the contralateral upper lip; 2, stimulation of the contralateral half of the tongue; 3, stimulation of the ipsilateral half of the tongue; CG, central grey matter; R, red nucleus; MG, the medial geniculate nucleus; In, intermediate grey and white layers of the SC; Dp, deep layers of the SC.
280 low intensity mechanical stimulation basically confirm the findings from previous studies and therefore will not enter into the discussion.
The inhibitory response appeared as soon as the stimulus was applied and usually led to a complete halt of this spontaneous activity (Fig. 1E). Sometimes the response continued a short time after the stimulation had ceased. The response to morphine was tested on two nociceptive-specific cells and two W D R cells. Ten minutes after the morphine i.p. injection, the response to the high intensity mechanical stimulation of the receptive field decreased greatly or was completely blocked. The i.p. injection of naloxone always reinstated the responses of the cell to this stimulation. In the case of the W D R cells, the response to the low intensity stimulation was not affected (Fig. 4B,C).
Units activated by high intensity mechanical stimulation The most important aspect of this study is the evidence it brings showing the high incidence of nociceptive representation of the buccal cavity in the SC 67. The existence of nociceptive activities evoked from oral fields has rarely been mentioned. The responses to stimulation of the nostrils or the lips have sometimes been described 41'61'66. Responses to electrical stimulation of the rabbit periodontium have recently been described by Tabata and Karita 67 in the same part of the SC as in our study. However, in their study, the nociceptive character of the periodontal stimulation could not be demonstrated. No doubt it was possible in our study to observe a large number of units responding to oral and/or facial stimuli (59/61) because we used an inverted stereotaxic frame which allowed direct access to the facial and oral receptive fields. It is interesting to note that although Wiener and Hartline 71 emphasized the role of peri- and intraoral areas in the SC, they considered the inside of the mouth as inaccessible. The truly nociceptive character of the responses of our units seems beyond doubt. Indeed, only certain somatosensory units (Ns and W D R ) responded to noxious stimulations applied to their peripheral receptive fields. Moreover, these units did not respond when the noxious stimulation was applied outside the limits of their
Location of high threshold somatosensory units The localization of the units which responded to nociception is represented in Fig. 5. Eight units could not be located histologically. Thirty-nine units (including 4 fibres) were located within the boundaries of the SC, mainly in the intermediate and deep layers, and 14 units (including 2 fibres) were located in the mesencephalic reticular formation beneath the SC or in the pretectal area. Contrary to other reports 49, no particular organization appeared on the horizontal plane. DISCUSSION
Units responding to low intensity mechanical stimulation Except for the large representation of the buccal cavity in the SC, our results concerning the units responding to
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Fig. 5. Location of the units activated by high intensity mechanical stimuli. Left: diagram showing the units on a frontal section of the SC, 2 mm anterior to the interaural plane. Right: diagram sl~owing the units on a horizontal section of the SC. The locations of the receptive fields are indicated as following: ©, oral; t~, oral and facial: A. facial; 0, oral, facial and anterior part of the body; ~. anterior part of the body: [], posterior part of body;INI, all the body except the oral territory; n, all the body.
281 receptive field. The clear distinction between the responses observed after a light and after an intense mechanical stimulation of WDR receptive fields, coupled with the fact that the responses of some units were suppressed with a morphine injection 15 also confirm the truly nociceptive nature of the responses activated by high intensity mechanical stimulation. A link between the SC and pain has already been noted. Indeed, the stimulation of the mesencephalic projections of the contralateral spinotectal tract provokes a noxious sensation in man and behaviour indicating pain in the cat 51'64. Moreover, several microphysiological studies have shown that the SC contains WDR and Ns neurons presenting excitatory or inhibitory responses 4L 46,61,66. The percentage of LT, WDR, Ns inh and Ns units (LT 52%, WDR 8%, Ns inh 16%, Ns 24%) is close to that found in previous studies 46'61'66. Except for the oral location of their receptive fields, the functional properties of the nociceptive units in our study were similar to those of previous studies 46'61'66. Several observations of the functional organization of the SC have revealed a characteristic vertical somatovisuotopic arrangement. Indeed, different authors have shown that when an object is placed in contact with the integuments of a mouse or a hamster, two distinct types of units are activated simultaneously: visual in the superficial layers, and somatosensory in the intermediate and deep layers. Furthermore, these two groups of cells are located one directly above the other in the SC. This can be explained by the fact that with a reduced head mobility in these animals, the representation of each part of the body is located in a relatively fixed spot of the visual field 8A°'23"68. In the cat where the cephalic mobility is much greater, this anatomo-functional organization does not exist 33. As Weiner and Hartline ~7 have pointed out, the organization of the SC is also radial, with the connections between the different layers arranged like rays converging roughly in the cerebral aqueduct. This reveals the lateral part of the SC, or 'flank', which is characterized in the mouse and the rat by the absence of superficial layers 54,71. It was at this level that the units responding to stimulation of oral receptive fields were recorded in our study (Fig. 5). The absence of visual layers covering the 'flank' could be related to the fact that the animal cannot see the oral cavity71. The large number of nociceptive inputs coming from the oral cavity that we recorded in this part of the SC supports the idea of its functional specificity.
The origin of nociceptive inputs to the superior colliculus The predominance of units which are activated by the stimulation of the orofacial region can only be possible because of the existence of the numerous projections
from the TSC into the SC 7's'44'48"60, In the rat, 3 of the 4 divisions of the TSC, the nucleus principalis, the subnuclei oralis and interpolaris project into the intermediate and deep layers of the anterior two-thirds of the contralateral SC 2'7'8'29'44'63'72. It is probable that the activities recorded in the SC after nociceptive stimulation of an oral field depends on a relay in the subnucleus oralis. Indeed, although the subnucleus caudalis contains neurons activated by nociceptive orofacial stimulation 25' 36,53,62, it is the only one of the 4 divisions of the TSC which does not project into the SC. On the other hand, the subnucleus oralis which sends numerous efferents into the intermediate and deep layers of the SC, is characterized by the presence of neurons activated by nociceptive stimulation of the oral region 4'14A5'16'55'73. Furthermore, units of this trigeminal division can be activated antidromically from the SC 2. However, the possibility of indirect trigeminocollicular projections via, for example, the reticular formation cannot be ruled out 8. Could the nociceptive activities of the SC be involved in the elaboration of noxious oral sensation? Supporting this hypothesis is the fact that the subnucleus oralis seems to play a role in this function as recent experiments have shown 4'6'12'14'15'27'33'36'38'55'62'70'76. Considering the findings from our study showing the presence of many oral nociceptive activities in the SC, there does seem to be a possibility that the noxious inputs passing through the subnucleus oralis may reach the thalamus via a supplementary relay located in the intermediate and deep layers of the SC. The very small number of direct projections from this division to the thalamus and the existence of collicular efferents to the diencephalon, and in particular to the thalamus, would seem to favour this hypothesis 34' 37,42,75. However, the functional characteristics of the collicular units responding to nociceptive stimuli are too different from those of units observed in the TSC or in the thalamus for this hypothesis to be accepted. In fact, when the functional characteristics of the nociceptive collicular units are compared to those of trigeminal or thalamic units isolated during recordings carried out in the same laboratory, on the same animal and under identical conditions of anaesthesia 15,55, the peripheral fields appear generally larger sometimes including the whole trigeminal territory (10) or sometimes extending out to the body (5), and the inhibitory or discontinuous fields appear more frequently.
Superior colliculus and behaviour The importance of the role of the tectum in behaviour has been demonstrated many times. Experimental lesions of the SC in the rat always suppress the contralateral rotation movement of the body, of the head and eyes, but also the oral motor function, in response to tactile, visual
282 or acoustic stimuli 17As'2°. Results from recent studies 8"22'29'57'75 and the discovery in our study of a large number of collicular units activated by oral stimuli, either tactile, nociceptive or proprioceptive, suggest that the tectum could be involved in chewing and associated behaviours. Systemic administration of dopamine agonists 2~'28 or the section of the striato-nigral pathways 32'43 provokes abnormal motor behaviour 13'47. In the rat in particular, the characteristic licking and chewing disappear as soon as the SC is destroyed 56. The inhibitory influence of the substantia nigra pars reticulata on the motor pathways from the tectum to the nuclei of the cranial nerves has been clearly demonstrated 11'35 and probably also concerns oral motor activity of collicular origin. The oral stereotyped behaviour induced by the destruction of the inhibitory G A BAergic nigrotectal pathways 3°'45'5°'69 would therefore be due to the functioning of collicular mechanisms released by the lifting of the nigral inhibitory control. Although the precise pathways allowing these oral behaviours are still unknown, the intermediate and deep layers seem to play a leading role since: (1) they contain as we have shown a large number of units activated by the stimulation of oral peripheral fields; (2) they receive nigrotectal efferentsT4; (3) an injection of a G A B A antagonist, picrotoxin, in the deep layers, provokes a particularly clear stereotyped oral behaviour58; (4) the activation of these layers by electrical stimulation provokes 'biting movements'~9; and (5) the tecto-reticulospinal bundle also originates in the intermediate and deep layers of the SC, and its reticular terminations surround
REFERENCES Albe-Fessard, D., Stutinsky, E and Liboudan, E, Atlas Stdr~otaxique du rat blanc, CNRS, Pards, 1971. 2 Azerad, J., Pollin, B. and Laplante, S., Projection of trigeminal sensory complex neurons to diencephalon and rectum: an anatomical and electrophysiological demonstration. In: B. Matthews and R.G. Hill (Eds.), Anatomical, Physiological and Pharmacological Aspect of Trigeminal Pain, (1982) p. 175. 3 Azerad, J., Woda, A. and Albe-Fessard, D., Identification dans les enregistrements par microdldctrodes de verre des activities recueillies au voisinage des axones et des corps cellulaires du complexe sensitif trigdminal, C.R. Acad. Sci., 285 (1977) 797-800. 4 Azerad, J., Woda, A. and Albe-Fessard, D., Physiological properties of neurons in different parts of the cat trigeminal sensory complex, Brain Research, 246 (1982) 7-21. 5 Baleydier, C. and Mauguiere, E, Projection of the ascending somesthesic pathways to the cat superior coUiculus visualized by the horseradish peroxidase technique, Exp. Brain Res., 31 (1978) 43-50. 6 Broton, J.G. and Rosenfeld, J.P., Effects of trigeminal tractotomy on facial thermal nociception in the rat, Brain Research, 333 (1985) 63-72. 7 Bruce, L.L, Mac Haffie, J.G. and Stein, B.E., The organisation of trigeminotectal and trigeminothalamic neurons in rodents: a double labeling study with fluorescent dyes, J. Comp. Neurol. 1
the motor nuclei of the V and VII 37"59. The role of the SC in oral behaviour could be the same as the one it has for the rest of the body with regard to external stimuli, i.e. attention, detection, and location of somatosensory stimuli if present in the buccal cavity. It should be pointed out concerning this last aspect that the use of motor reactions, protecting the intra- and perioral structures against nociceptive stimuli coming from outside the visual field, is of great survival value for the animal. The SC could also be involved in the exploration of a rostral area beyond the visual field. This area is very important for the rodent whose head is not very mobile in relation to the rest of the body 23 which is not the case for the cat. A precise analysis of this area is necessary in the control of oral motricity during the processes of food hunting and oral prehension, independent of the chewing 56. Finally, the SC could, considering the quantity of nociceptive afferents it receives, play a role in an arousal system, stimulating attention behaviours which involve orientating the head and eyes and possibly preparing the buccal cavity for an attack reaction. It should be remembered that it has been experimentally shown that ablation of the SC leads to the animal losing its attention with regard to noxious stimuli 9'64. Acknowledgements. The authors wish to thank R. Boyer, S. Millien and A.M. Moins-Gaydier for assistance with the manuscript preparation, M. Leroux for the photography and J. Cane for the English translation. The research was supported by grants from Fondation Dentaire de France.
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284 superior colliculus in rats, Brain Research, 215 (1981) 352-358. 57 Redgrave, P., Dean, P., Donohoe, T.E and Pope, S.G., Superior colliculus lesions selectively attenuate apomorphineinduced oral stereotypy: a possible role for the nigrotectal pathway, Brain Research, 196 (1980) 541-546. 58 Redgrave, P., Dean, P., Souki, W. and Lewis, G., Gnawing changes in reactivity produced by microinjection of picrotoxin into the superior colliculus of rats, Psychopharmacology, 75 (1981) 198-203. 59 Redgrave, P., Michel, I.J. and Dean, P., Descending projections from the superior colliculus in rat: a study using orthograde transport of wheat germ-agglutinin conjugated horseradish peroxidase, Exp. Brain Res., (1987) 147-167. 60 Rhoades, R.W., Organisation of somatosensory inputs to the deep colticular laminae in the golden hamster, Behav. Brain Res., 3 (1981) 201-202. 61 Rhoades, R.W., Mooney, R.D. and Jaequin, M.R., Complex somatosensory receptive fields of cells in the deep laminae of the hamster's superior colliculus, J. Neurosci., 3 (1983) 1342-1354. 62 Sessle, B.J. and Greenwood, L.F., Inputs to trigeminal brain stem neurones from facial, oral, tooth pulp and pharyngolaryngeal tissues. I. Responses to innocuous and noxious stimuli, Brain Research, 117 (1976) 211-226. 63 Silverman, J.D. and Kruger, L., Projection of the rat trigeminal sensory nuclear complex demonstrated by multiple fluorescent dye retrograde transport, Brain Research, 361 (1985) 383-388. 64 Spiegel, E.A., Kletzkin, M. and Szekely, E.G., Pain reactions upon stimulation of tectum mesencephali, J. Neuropathol. Exp. Neurol., 13 (1954) 212-226. 65 Stein, B.E., Castro, B.M. and Kruger, L., Superior colliculus: visuotopic-somatotopic overlap, Science, 189 (1975) 224-226. 66 Stein, B.E. and Dixon, J.P., Superior colliculus cells respond to
noxious stimuli, Brain Research, 158 (1978) 65-73. 67 Tabata, T. and Karita, K., Laminar distribution and the response of superior colliculus neurons to stimulation of the periodontal ligament in the rabbit, Exp. Neurol., 80 (1983) 663-671. 68 Tiao, Y.C. and Blakemore, C., Functional organization in the superior colliculus of the golden hamster, J. Comp. Neurol., 168 (1976) 483-504. 69 Vincent, S.R., Hattori, T. and Mac Geer, E.G., The nigrotectal projection: a biochemical and ultrastructural characterization, Brain Research, 151 (1978) 159-164. 70 Vyklicky, L. and Keller, D., Central projection of tooth pulp primary afferents in the cat, Acta Neurobiol. Exp., 33 (1973) 803-809. 71 Wiener, S.I. and Hartline, P.H., Perioral somatosensory but not visual inputs to the flank of the mouse superior colliculus, Neuroscience, 21 (1987) 557-564. 72 Wiberg, M., Westman, J. and Blomqvist, A., The projection to the mesencephalon from the sensory trigeminal nuclei, an anatomical study in the cat, Brain Research, 399 (1986) 51-68. 73 Woda, A., Azerad, J. and Albe-Fessard, D., Mapping of the trigeminal sensory complex of the cat. Characterisation of its neurons by stimulations of peripheral field, dental pulp afferents and thalamic projections, J. Physiol. (Paris), 73 (1977) 367-378. 74 Wright, A.K. and Arbuthnott, G.W., Non-dopamine containing efferents of substantia nigra: the pathway to the lower brain stem, J. Neural Transm., 47 (1980) 221-226. 75 Yamasaki, D.S.G., Rauthamer, G.M.K. and Rhoades, R.W., Superior collicular projection to intralaminar thalamus in rat, Brain Research, 378 (1986) 222-233. 76 Young, R.F. and Perryman, K.M., Neuronal responses in rostral trigeminal brainstem nuclei of macaque monkeys after chronic trigeminal tractotomy, J. Neurosurg., 65 (1986) 508-516.
Brain Research, 549 (1991) 275-284 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 ADONIS 000689939116617X BRES 16617
Oral nociceptive activity in the rat superior colliculus P. Auroy, B. Irthum and A. Woda Laboratoire de Physiologie Orofaciale, Facultd de Chirurgie Dentaire, Clermont Ferrand (France) (Accepted 11 December 1990) Key words: Nociception; Orofacial receptive field; Superior colliculus, Rat
Single units were recorded using extracellular glass microelectrodes in all laminae of the superior colliculus of the rat under haiothane nitrous oxide anaesthesia. Fifty-one units were encountered which responded to a low intensity mechanical stimulus applied to a contralaterai or bilateral field located in the oral sphere (intraoral 11, perioral 16), on the face (29) or on the rest of the body (21). Sixteen units responded to a jaw movement. Sixty-one cells were recorded which were preferentially (10) or only (51) activated (30) or inhibited (21) by noxious stimuli. Contralateral or bilateral mechanoreceptive fields located in intraoral (34) and perioral (35) areas were frequent. There is therefore a high incidence of the nociceptive representation of the mouth in the superior colliculus. The other functional properties of the nociceptive units were similar to those reported in other studies. From the subsequent histological localization of the recorded units, it appeared that the nociceptive projections from the intraoral and perioral regions to the superior colliculus reach the lateral part of the intermediate and deep layers of the superior colliculus.
INTRODUCTION The architecture of the superior colliculus (SC) in the rat is characterized by a laminar organization with alternating layers of white and grey matter. The upper layers are involved in vision whereas the intermediate and deep layers are multimodal with somesthesia predominating. M a n y anatomical studies have established that the trigeminal sensory complex (TSC) projects heavily into the superior colliculus. In particular, the subnuclei interpolaris and oralis project into the rostral two thirds of the intermediate and deep layers of the contralateral SC in the cat 26 as well as in different rodents 2'7'8"39"4°'44. U n i t recordings in the deep layers of the SC have also confirmed the existence of a representation of trigeminal somesthesia and especially of the face and vibrissae 1°'24'31,33,52,65,68,71. Moreover, stimulation of the mesencephalic projections of the spinotectal tract produces pain in m a n and behaviours indicative of pain in the cat 51'64. Microelectrode studies in the hamster 36" 46,61,66 and in the rat 49 have shown that the SC contains n e u r o n s which respond preferentially, or only, to nociceptive stimuli. Because of these facts and also because of the large representation of the mouth in the subnucleus oralis 4'16, the presence in the SC, of n e u r o n s activated by nociceptive stimulation of the intra- or perioral trigeminal field
can be postulated. Consequently, the aim of this study was to investigate the receptive fields and the functional characteristics of the collicular units responding to high intensity somesthesic stimulation.
MATERIALS AND METHODS Thirty-four male Sprague-Dawley rats weighing between 220 and 280 g were used for this experiment. These weight limits enabled us to use the stereotaxic coordinates given in the atlas of Albe-Fessard et al. 1. Anaesthesia All animals were anaesthetized initially with an intraperitoneal (i.p.) injection of Ketamine hydrochloride (120 mg/kg) in order for a tracheotomy to be carried out. Anaesthesia was maintained during surgery with a mixture of 1/3 02, 2/3 N20 and halothane at a concentration of 1.5%. This halothane concentration was then reduced and maintained at 0.5% during the recording periods. The animals were allowed to breathe spontaneously. The level of anaesthesia was systematically checked by an electro-corticogramme (EcoG) recorded longitudinally using two silver ball electrodes applied to the dura. Thus, all the units in this study were recorded during a stable and moderate state of anaesthesia, which was sufficient however to avoid clinical or electrocortical signs of suffering, i.e. arousal, caused by the application of noxious stimuli. The EcoG usually consisted of a 4-5 Hz theta rhythm associated with a few spindles. The vascularization of the peripheral cutaneous receptive fields was checked by observing the colour of the extremities and their ability to return quickly to their previous state after application of pressure. The central temperature was maintained at 37-38 °C with a homeothermic blanket system. The cardiac rhythm was continuously monitored.
Correspondence: A. Woda, Laboratoire de Physiologic Orofaciale, Facult6 de Chirurgie Dentaire, 11 Bd Charles de Gaulle, 63000 Clermont Ferrand, France.
276
Surgical preparation A craniectomy was carried out with a drill, exposing a 5 mm rostro-caudal extent of the dura mater directly above the position of the SC, -1 - + 4 mm according to the stereotaxic coordinates of Albe-Fessard et al.l, and laterally 4 mm from either side of the midline. The dura mater was incised and folded back onto the sides of the craniectomy and over the superior sagittal sinus which was thus protected. On the first 6 rats, an occipital lobectomy was performed by aspiration of the cerebral tissue revealing the surface of the SC. On the following 28 rats, the SC was reached by a transcortical electrode penetration.
with a binocular microscope. An iontophoretic injection (15/tA, 20 min) of a saline solution of Pontamine blue was performed at the end of each track. The resulting blue points permitted the localization of the collicular recording sites which were then plotted onto the corresponding maps of the stereotaxic atlas of AlbeFessard et al. 1 (frontal planes A 1.2-A 2.9).
Recordings Recordings were made using glass micropipettes of a resistance of 6-10 M~2, filled with a mixture of 5% NaCI and Pontamine sky blue. Penetration of the upper layers of the SC was guided by the presence of cells responding to visual stimuli. As the microelectrode was advanced deeper into the SC, visual, acoustic, noxious and non-noxious mechanical stimuli were systematically applied in search for evoked activity. If evoked or spontaneous activity of a single unit was clearly differentiated, then mechanical stimuli were further applied to all cutaneous and mucosal areas so as to characterize the unit. More detailed descriptions of the methodology used for stimulation and recording can be found elsewhere 15'
m e c h a n i c a l , acoustic o r visual stimuli w e r e r e c o r d e d .
RESULTS Two
16,55
The sensory stimuli included visual stimuli, such as the turning-on or switching-off a light and the movement of a light across the visual field, and also acoustic stimuli such as the clinking of metal objects, whistling or handclapping. Non-noxious mechanical stimuli included localized air puffs, brushing with a soft paint brush or rubbing with a blunt wooded probe. Noxious stimuli included heavy pressure, pinpricks or pinching with fine forceps (tip area 1 mm 2) which produced forces of 0.5-1.5 kg and provoked noxious sensations when applied to the experimenter's skin. The extent of the unit's receptive field was determined and drawn, and its location was designated in terms of its involvement in intraoral regions (lip, lingual, palatal or cheek mucosa, periodontium), perioral regions (hairy part of the lip, muzzle), facial regions or other parts of the body (see Fig. 7 in Dallel et a1.15). The units' responses to the mechanical stimuli allowed us to classify them into 4 groups. (1) Low threshold (LT) mechanoreceplive units which responded to hair movement, touch and light pressure applied to the skin surface. They showed no increase in discharge frequency with more intense stimuli and these were considered to be non-nociceptive tactile units. (2) Wide dynamic range (WDR) units which responded to low-intensity and highintensity cutaneous mechanical stimuli. They showed an increase in discharge frequency with more intense stimuli and were considered to be non-specific nociceptive units. (3) Units which were only activated by high-intensity mechanical stimuli (heavy pressure and/or pinch) and were considered to be nociceptive specific (Ns) units. (4) Units which exhibited a spontaneous activity that decreased or was suppressed following a high-intensity mechanical stimulation. They were called inhibitory nociceptive specific units (Ns inh). The differentiation of the recorded units into fibres and soma was made according to the criteria defined by Azerad et al. 3. Some units were analyzed 10 min after an injection of morphine (5 mg/kg i.p.), then 10 min after an injection of naloxone (0.5 mg/kg i.p.) in order to confirm their nociceptive character. The responses were recorded on an oscilloscope screen in the shape of a peristimulus time histogram and were photographed as previously described 15.
Location of the recorded units After sacrificing the animal, the brain was removed and placed in a fixative 10% formalin solution. The mesencephalon was then sliced into frontal serial sections of 100/~m which for 15 rats were stained using the Kluver-Barrera technique so as to show the laminated structure of the SC. The Nissi-staining method (Cresyl violet) was used for the other animals. The slices were examined
hundred
and
twenty-six
units
responding
to
Sixty-seven units w e r e a c t i v a t e d by low intensity m e c h a n ical stimuli (tactile) and 61 units w e r e a c t i v a t e d by high intensity m e c h a n i c a l stimuli ( n o c i c e p t i v e ) (Table I). A l t h o u g h this study was n o t d i r e c t l y c o n c e r n e d with the f u n c t i o n a l p r o p e r t i e s of the n o n - s o m e s t h e s i c units, we r e c o r d e d 91 units (89 s o m a and 2 fibres) which r e s p o n d e d to visual stimuli (Fig. 1A). F o u r t e e n units w e r e a c t i v a t e d by acoustic stimuli. F i v e units with a visual r e s p o n s e and 2 units with an a u d i t o r y r e s p o n s e w e r e also a c t i v a t e d by low intensity
(4 times)
or
high
intensity
(3 times)
m e c h a n i c a l stimulation. T h e l o c a t i o n of the r e c o r d i n g sites shows that the units r e s p o n d i n g to visual stimulation w e r e m a i n l y f o u n d in the u p p e r layers, w h e r e a s cells in the layers b e l o w w e r e p r e d o m i n a n t l y a c t i v a t e d by auditory and s o m a t o s e n s o r y
stimuli.
Units responding
to
a u d i t o r y stimuli w e r e f o u n d m a i n l y in t h e p o s t e r i o r and lateral parts,
w h e r e a s the units r e s p o n d i n g
to visual
stimuli w e r e l o c a t e d m o r e in t h e a n t e r i o r and m e d i a l parts.
Units activated by low intensity mechanical stimuli Sixty-seven units (62 s o m a and 5 fibres) r e s p o n d e d to light m e c h a n i c a l stimuli. F i f t y - o n e units w e r e a c t i v a t e d by stimulation of the oral m u c o s a , the skin surface, hairs and vibrissae, and 16 units r e s p o n d e d to the m o b i l i z a t i o n of the t e m p o r o - m a n d i b u l a r j o i n t ( T M J ) .
TABLE I
Distribution of the recorded SC units according to the topographical location of their receptivefield It must be noted that units having a receptive field involving more than one of the mentioned regions of the body, have been counted more than once. The number of recorded units is specifed in the first column.
Number ofcells 67 10 30 21
LT WDR Ns Nsinh
lntraoral
Perioral Facial Body Jaw movement
11 3 12 2
16 3 20 19
29 4 16 11
21 1 5 3
16 1 0 0
277
Fig. 1. Different examples of responses obtained from recordings of SC units. The spikes which are shown in A are displayed in the shape of a peristimulus time histogram in B-E; each dot represents one spike and each bin lasts 1.5 s. The onset and offset of the visual or low intensity mechanical stimulations are represented by the empty arrows. The onset and offset of the high intensity mechanical stimulations are shown by the white arrows. The recordings represented in A, B, C, D, E are typical of responses obtained from cells called visual (V), low threshold (LT) somatosensory, low and high threshold somatosensory (WDR), nociceptive specific (Ns) or nociceptive specific presenting an inhibitory response (Ns inh). The diagrams represent the peripheral fields and the location of the cells on a frontal section of the SC. Fig. 1E shows the response to the stimulation of the contralateral side of the tongue (1) and of the lower lip (2). G, central grey; R, red nucleus; MG, medial geniculate nucleus; In, intermediate grey and white layers of the SC; Dp, deep layers of the SC; 3, nucleus of the oculomotor nerve.
Cutaneo-mucosal units The mechanoreceptive fields were located 36 times in the half of the body contralateral to the recording electrode; 15 times were these fields bilateral with the response being predominantly contralateral. The mechanoreceptive fields were considered as oral, i.e. intra- and periora115, when located in the mouth, on the muzzle or on the hairy part of the lips. The receptive fields were situated in the intraoral region (11 times), in the perioral region (16 times), in the facial region (29 times, 13 times concerning exclusively the vibrissae), and on the rest of the body (21 times). The functional characteristics of these units were generally those of cells responding to low intensity mechanical stimulation such as a light touching of the hairs or vibrissae, but sometimes it was necessary to press the skin with a blunt wooden probe in order to obtain a response. The responses were not adaptable (Fig. 1B) or were of the o n - o f f type. Of the 4 neurons responding with an inhibition of their spontaneous activity, 2 had only an inhibitory mechanoreceptive field which was
contralateral and clearly defined and 2 had both an inhibitory field and a wider spread, less well-defined excitatory field. Four neurons having a facial receptive field including the vibrissae, were also activated by acoustic (2 units) or visual (2 units) stimuli.
Units responding to the jaw movement It is difficult to differentiate between the jaw movement responses and those activities evoked by an irritation when a neuron is displaced in relation to the electrode tip during the jaw movement. For this reason, the jaw movement responses were only considered when they satisfied the 3 following criteria: (1) there was a response to a slight jaw movement; (2) there was no change in amplitude of the action potentials during the jaw movement; and (3) it was impossible to produce a cell activity by any other pressure likely to produce a head movement. Ten neurons were activated by a single jaw movement, giving either an increase (6 units) or a decrease (4 units) in their spontaneous discharge frequency. Three neurons were activated by a jaw move-
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-1 Fig. 2. Location of the units activated by low intensity mechanical stimuli. Left: diagram showing the units on a frontal section of the SC, 2 mm anterior to the interaural plane. Right: diagram showing the units on a horizontal section of the SC. The locations of the receptive fields are indicated as following: O, oral; ~), oral and facial: A, facial; O, oral, facial, and anterior part of the body; ~, anterior part of the body; ii, posterior part of the body; l , all the body: *. jaw movement. m e n t in 2 opposite directions giving an increase or decrease in their discharge frequency. Two neurons were activated by jaw m o v e m e n t s in several directions producing the same change in neuronal activity. O n e neuron r e s p o n d e d to both a tactile stimulation of a contralateral oral field and to a jaw m o v e m e n t , and another r e s p o n d e d to nociceptive stimulation and to a jaw m o v e m e n t (see Fig. 4). These units were not sensitive to jaw positions but to jaw movements. O p e n i n g the mouth for example p r o d u c e d a regular and p r o l o n g e d discharge which varied with the a m p l i t u d e and speed of the movement. No a t t e m p t was m a d e to differentiate between the origins (muscular, articular etc.) of these proprioceptive responses.
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Location of low threshold somatosensory units The location of the recording site was only possible for 43 units (Fig. 2). Thirty of t h e m were found in the i n t e r m e d i a t e and deep layers of the SC. Seventeen out of 19 cells having oral and/or facial fields were located in the rostral part of the SC, 8 units with a somatic field which excluded the oral sphere or the face were o b s e r v e d in the caudal part, but a significant n u m b e r (7) were also observed in a m o r e rostral location. Neurons activated by a jaw m o v e m e n t were observed scattered in the rostrocaudal direction.
Units activated by high intensity mechanical stimuli Sixty-one units (54 s o m a and 7 fibres, 10 W D R , 30 Ns and 21 Ns inh) r e s p o n d e d to intense mechanical stimu-
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Fig. 3. Receptive fields of the units activated by high intensity mechanical stimuli. The different locations of the receptive fields have been represented as following: O, oral; F, facial; A, anterior part of body; P, posterior part of body. The oral sphere is shown in black. The number of units belonging to each of these 4 groups is indicated (n).
279 The 10 W D R units had a spontaneous, irregular activity between 0 and 5 Hz (Fig. 1C) which would seem to be a characteristic of these W D R collicular units 66. They responded distinctly to a slight stimulation of a cutaneous or oral mucosal field, or of the periodontium (6 units), to m o v e m e n t of the vibrissae (one unit) or of the jaw (one unit). Intense mechanical stimulation provoked an increase in the response which sometimes continued after the stimulation had ceased 46. It consisted of an excitation in 9 cases (Fig. 1C) and of an inhibition in the one case of a neuron which displayed high level spontaneous activity. The 51 nociceptive-specific units were activated only by intense mechanical stimuli. Thirty units responded with an increase in their baseline activity. This response was composed of an emission of high frequency bursts of action potential and was followed in most cases by a post-discharge (Fig. 1D). Three units (1 oral, 2 orofacial) also responded to visual stimuli. Twenty-one nociceptivespecific units responded with an inhibition of their spontaneous activity which frequently went above 20 Hz.
lation. The receptive fields of these units were mainly located in the oral and facial regions (Fig. 3). A m o n g the 48 units which had an oral receptive field (Fig. 3), 17 (12 Ns, 3 W D R , and 2 Ns inh) had all or part of their receptive field inside the mouth. The receptive fields situated in the orofacial region were generally clearly defined, of small surface area and involved: 1 part only of the trigeminal territory (26 times), 2 parts of the trigeminal territory (18 times), and 3 parts of the trigeminal territory (10 times). More rarely a diffused field was observed (7 times), sometimes bilateral, showing zones of varying sensitivity. When covering a part or all of the rest of the body, they were generally large and were not clearly defined. The receptive fields were contralateral to the recording electrode (33 units), ipsilateral (2 units) or bilateral (26 units). In this last case, we sometimes saw (8 units) that there were more responses from the contralateral part of the field (Fig. 4A). Some were discontinuous and were made up of zones which, when stimulated, resulted sometimes in an activation of the unit and sometimes in an inhibition.
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Fig. 4. Example of a WDR cell response. Left: the diagrams represent the location of the cell and the territory of its receptive field. Right: the recordings of this unit displayed as a peristimulus time histogram; the onset and offset of the nociceptive stimuli are shown by the white arrows; the beginning and end of the jaw movement are shown by the empty arrows. A: a peristimulus time histogram showing the responses before the injection. B: responses obtained 18 min after the morphine injection. C: responses obtained 10 min after the naloxone injection. 1, stimulation of the contralateral upper lip; 2, stimulation of the contralateral half of the tongue; 3, stimulation of the ipsilateral half of the tongue; CG, central grey matter; R, red nucleus; MG, the medial geniculate nucleus; In, intermediate grey and white layers of the SC; Dp, deep layers of the SC.
280 low intensity mechanical stimulation basically confirm the findings from previous studies and therefore will not enter into the discussion.
The inhibitory response appeared as soon as the stimulus was applied and usually led to a complete halt of this spontaneous activity (Fig. 1E). Sometimes the response continued a short time after the stimulation had ceased. The response to morphine was tested on two nociceptive-specific cells and two W D R cells. Ten minutes after the morphine i.p. injection, the response to the high intensity mechanical stimulation of the receptive field decreased greatly or was completely blocked. The i.p. injection of naloxone always reinstated the responses of the cell to this stimulation. In the case of the W D R cells, the response to the low intensity stimulation was not affected (Fig. 4B,C).
Units activated by high intensity mechanical stimulation The most important aspect of this study is the evidence it brings showing the high incidence of nociceptive representation of the buccal cavity in the SC 67. The existence of nociceptive activities evoked from oral fields has rarely been mentioned. The responses to stimulation of the nostrils or the lips have sometimes been described 41'61'66. Responses to electrical stimulation of the rabbit periodontium have recently been described by Tabata and Karita 67 in the same part of the SC as in our study. However, in their study, the nociceptive character of the periodontal stimulation could not be demonstrated. No doubt it was possible in our study to observe a large number of units responding to oral and/or facial stimuli (59/61) because we used an inverted stereotaxic frame which allowed direct access to the facial and oral receptive fields. It is interesting to note that although Wiener and Hartline 71 emphasized the role of peri- and intraoral areas in the SC, they considered the inside of the mouth as inaccessible. The truly nociceptive character of the responses of our units seems beyond doubt. Indeed, only certain somatosensory units (Ns and W D R ) responded to noxious stimulations applied to their peripheral receptive fields. Moreover, these units did not respond when the noxious stimulation was applied outside the limits of their
Location of high threshold somatosensory units The localization of the units which responded to nociception is represented in Fig. 5. Eight units could not be located histologically. Thirty-nine units (including 4 fibres) were located within the boundaries of the SC, mainly in the intermediate and deep layers, and 14 units (including 2 fibres) were located in the mesencephalic reticular formation beneath the SC or in the pretectal area. Contrary to other reports 49, no particular organization appeared on the horizontal plane. DISCUSSION
Units responding to low intensity mechanical stimulation Except for the large representation of the buccal cavity in the SC, our results concerning the units responding to
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Fig. 5. Location of the units activated by high intensity mechanical stimuli. Left: diagram showing the units on a frontal section of the SC, 2 mm anterior to the interaural plane. Right: diagram sl~owing the units on a horizontal section of the SC. The locations of the receptive fields are indicated as following: ©, oral; t~, oral and facial: A. facial; 0, oral, facial and anterior part of the body; ~. anterior part of the body: [], posterior part of body;INI, all the body except the oral territory; n, all the body.
281 receptive field. The clear distinction between the responses observed after a light and after an intense mechanical stimulation of WDR receptive fields, coupled with the fact that the responses of some units were suppressed with a morphine injection 15 also confirm the truly nociceptive nature of the responses activated by high intensity mechanical stimulation. A link between the SC and pain has already been noted. Indeed, the stimulation of the mesencephalic projections of the contralateral spinotectal tract provokes a noxious sensation in man and behaviour indicating pain in the cat 51'64. Moreover, several microphysiological studies have shown that the SC contains WDR and Ns neurons presenting excitatory or inhibitory responses 4L 46,61,66. The percentage of LT, WDR, Ns inh and Ns units (LT 52%, WDR 8%, Ns inh 16%, Ns 24%) is close to that found in previous studies 46'61'66. Except for the oral location of their receptive fields, the functional properties of the nociceptive units in our study were similar to those of previous studies 46'61'66. Several observations of the functional organization of the SC have revealed a characteristic vertical somatovisuotopic arrangement. Indeed, different authors have shown that when an object is placed in contact with the integuments of a mouse or a hamster, two distinct types of units are activated simultaneously: visual in the superficial layers, and somatosensory in the intermediate and deep layers. Furthermore, these two groups of cells are located one directly above the other in the SC. This can be explained by the fact that with a reduced head mobility in these animals, the representation of each part of the body is located in a relatively fixed spot of the visual field 8A°'23"68. In the cat where the cephalic mobility is much greater, this anatomo-functional organization does not exist 33. As Weiner and Hartline ~7 have pointed out, the organization of the SC is also radial, with the connections between the different layers arranged like rays converging roughly in the cerebral aqueduct. This reveals the lateral part of the SC, or 'flank', which is characterized in the mouse and the rat by the absence of superficial layers 54,71. It was at this level that the units responding to stimulation of oral receptive fields were recorded in our study (Fig. 5). The absence of visual layers covering the 'flank' could be related to the fact that the animal cannot see the oral cavity71. The large number of nociceptive inputs coming from the oral cavity that we recorded in this part of the SC supports the idea of its functional specificity.
The origin of nociceptive inputs to the superior colliculus The predominance of units which are activated by the stimulation of the orofacial region can only be possible because of the existence of the numerous projections
from the TSC into the SC 7's'44'48"60, In the rat, 3 of the 4 divisions of the TSC, the nucleus principalis, the subnuclei oralis and interpolaris project into the intermediate and deep layers of the anterior two-thirds of the contralateral SC 2'7'8'29'44'63'72. It is probable that the activities recorded in the SC after nociceptive stimulation of an oral field depends on a relay in the subnucleus oralis. Indeed, although the subnucleus caudalis contains neurons activated by nociceptive orofacial stimulation 25' 36,53,62, it is the only one of the 4 divisions of the TSC which does not project into the SC. On the other hand, the subnucleus oralis which sends numerous efferents into the intermediate and deep layers of the SC, is characterized by the presence of neurons activated by nociceptive stimulation of the oral region 4'14A5'16'55'73. Furthermore, units of this trigeminal division can be activated antidromically from the SC 2. However, the possibility of indirect trigeminocollicular projections via, for example, the reticular formation cannot be ruled out 8. Could the nociceptive activities of the SC be involved in the elaboration of noxious oral sensation? Supporting this hypothesis is the fact that the subnucleus oralis seems to play a role in this function as recent experiments have shown 4'6'12'14'15'27'33'36'38'55'62'70'76. Considering the findings from our study showing the presence of many oral nociceptive activities in the SC, there does seem to be a possibility that the noxious inputs passing through the subnucleus oralis may reach the thalamus via a supplementary relay located in the intermediate and deep layers of the SC. The very small number of direct projections from this division to the thalamus and the existence of collicular efferents to the diencephalon, and in particular to the thalamus, would seem to favour this hypothesis 34' 37,42,75. However, the functional characteristics of the collicular units responding to nociceptive stimuli are too different from those of units observed in the TSC or in the thalamus for this hypothesis to be accepted. In fact, when the functional characteristics of the nociceptive collicular units are compared to those of trigeminal or thalamic units isolated during recordings carried out in the same laboratory, on the same animal and under identical conditions of anaesthesia 15,55, the peripheral fields appear generally larger sometimes including the whole trigeminal territory (10) or sometimes extending out to the body (5), and the inhibitory or discontinuous fields appear more frequently.
Superior colliculus and behaviour The importance of the role of the tectum in behaviour has been demonstrated many times. Experimental lesions of the SC in the rat always suppress the contralateral rotation movement of the body, of the head and eyes, but also the oral motor function, in response to tactile, visual
282 or acoustic stimuli 17As'2°. Results from recent studies 8"22'29'57'75 and the discovery in our study of a large number of collicular units activated by oral stimuli, either tactile, nociceptive or proprioceptive, suggest that the tectum could be involved in chewing and associated behaviours. Systemic administration of dopamine agonists 2~'28 or the section of the striato-nigral pathways 32'43 provokes abnormal motor behaviour 13'47. In the rat in particular, the characteristic licking and chewing disappear as soon as the SC is destroyed 56. The inhibitory influence of the substantia nigra pars reticulata on the motor pathways from the tectum to the nuclei of the cranial nerves has been clearly demonstrated 11'35 and probably also concerns oral motor activity of collicular origin. The oral stereotyped behaviour induced by the destruction of the inhibitory G A BAergic nigrotectal pathways 3°'45'5°'69 would therefore be due to the functioning of collicular mechanisms released by the lifting of the nigral inhibitory control. Although the precise pathways allowing these oral behaviours are still unknown, the intermediate and deep layers seem to play a leading role since: (1) they contain as we have shown a large number of units activated by the stimulation of oral peripheral fields; (2) they receive nigrotectal efferentsT4; (3) an injection of a G A B A antagonist, picrotoxin, in the deep layers, provokes a particularly clear stereotyped oral behaviour58; (4) the activation of these layers by electrical stimulation provokes 'biting movements'~9; and (5) the tecto-reticulospinal bundle also originates in the intermediate and deep layers of the SC, and its reticular terminations surround
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the motor nuclei of the V and VII 37"59. The role of the SC in oral behaviour could be the same as the one it has for the rest of the body with regard to external stimuli, i.e. attention, detection, and location of somatosensory stimuli if present in the buccal cavity. It should be pointed out concerning this last aspect that the use of motor reactions, protecting the intra- and perioral structures against nociceptive stimuli coming from outside the visual field, is of great survival value for the animal. The SC could also be involved in the exploration of a rostral area beyond the visual field. This area is very important for the rodent whose head is not very mobile in relation to the rest of the body 23 which is not the case for the cat. A precise analysis of this area is necessary in the control of oral motricity during the processes of food hunting and oral prehension, independent of the chewing 56. Finally, the SC could, considering the quantity of nociceptive afferents it receives, play a role in an arousal system, stimulating attention behaviours which involve orientating the head and eyes and possibly preparing the buccal cavity for an attack reaction. It should be remembered that it has been experimentally shown that ablation of the SC leads to the animal losing its attention with regard to noxious stimuli 9'64. Acknowledgements. The authors wish to thank R. Boyer, S. Millien and A.M. Moins-Gaydier for assistance with the manuscript preparation, M. Leroux for the photography and J. Cane for the English translation. The research was supported by grants from Fondation Dentaire de France.
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