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Suppression of noxious thermal evoked responses in thalamic central lateral nucleus by cortical spreading depression
199
Pain, 35 (1988) 199-204 Elsevier
PA1 01296
Suppression of noxious thermal evoked responses in thalamic central lateral nucleus by cortical spreading depression Miguel CondCs-Lara
* and Imelda Omaha Zapata
**
* Departamento
de Neurofisiologia, Diuisibn de Investigaciones en Neurociencias. Institute Mexicano de Psiquiatria, Calzada M&co-Xochimilco 101, Mexico, D.F. 14370 (Mexico), and * * Coordinacibn de Estudios de Postgrado, Inuestigaci6n y Desarrollo Acadbnico ENEP, Zaragora, UNA M, Mexico (Mexico) (Received
17 February
1988, revision received 9 May 1988, accepted
15 June 1988)
s-w
Several thalamic nuclei are associated with the processing of pain information and are influenced by’cortical actions. This paper demonstrates a cortical influence upon the medial thalamic nuclei unit activity evoked by thermal noxious stimulation in rats. We studied the effects of cortical spreading depression (CSD) upon the responses of the centralis lateralis (CL) nucleus of the medial thalamus to noxious heat stimulation. Urethane was used as anaesthetic. Cells responding to noxious stimulation were localized in the dorsal portion of the CL. These cells responded like polymodal or nociceptive specific units in the spinal cord and exhibited their highest discharge frequency with noxious stimuli. When CSD is propagated and affects the medial frontal cortex it blocks the responses evoked in CL cells by noxious stimulation. Cortical cells located at this level also exhibited responses evoked by noxious stimulation. Our results suggest a cortical facilitatory control upon the noxious responses recorded in the CL cells. Key words:
Thalamic
nuclei;
Noxious
thermal
evoked
responses;
Introduction Cells located in the medial thalamus (parafascicentralis medialis, centralis lateralis, cularis, centrum medianum nuclei) respond to noxious peripheral stimulation in the rat [7,23], cat [1,14,18,22] and monkey [ll]. The role of these neurons in processing pain information was recently reviewed [5]. It is claimed [6,7] that the medial thalamic cells are under the control of an ascending pain modulation system producing
Cortical
influence;
Rats
analgesia. This could originate with the projection from neurons located within the periaqueductal gray of the midbrain containing serotonin, a neurotransmitter known to be involved in analgesia
[91. The cerebral cortex (Cx) has also been shown to play a role in pain modulation [6,15-171. It has been shown to exert a facilitatory action over medial thalamic cells [4,8,12,24,25]; however, electrical stimulation of the cortex suppresses the re; sponses of medial thalamic cells to noxious stimuli
[61.
Correspondence to: Dr. Miguel Condts-Lara, Departamento de Neurofisiologia, Divisi6n de Investigaciones en Neurociencias, Instituto Mexican0 de Psiquiatria, Calzada MtxicoXochimilco 101. Mexico, D.F. 14370, Mexico. 0304-3959/88/$03.50
The present study explored further the role of the cerebral cortex in the modulation of responses to noxious stimuli in the medial thalamus. For this we used a transient and reversible blockage of cortical activity by means of the cortical spreading depression technique [10,20,21].
0 1988 Elsevier Science Publishers B.V. (Biomedical Division)
Xi! Methods Twenty-two male albino rats (Wistar) weighing 250-300 g were used. Subjects were anaesthetized with urethane (1500-2~ mg/kg i.p.) and placed in a stereotaxic apparatus. The stereotaxic coordinates and the incisor bar orientation were those used by Albe-Fessard et al. [3]. The head was shaved and the skull exposed. Two holes were drilled into the bone. One, at A 1.0 and L 2.0, was used for the application (of 60 set duratjon) of small pieces of paper (1 mm2) soaked in a KC1 solution (1 M) to produce cortical spreading depression (CSD). The other, made between A 4.5 and 10.5, and L 0.5-2.5, allowed us to place the electrodes for recording unit activity. We studied cells located in the cerebral cortex (Cx) and in the nuclei centralis lateralis (CL), ventralis lateralis (VL) and lateralis (L) of the thalamus. Single units were recorded using glass micropipettes filled with a 4R solution of pontamine blue in 1 M KC1 (impedance 8-10 MO). A systematic mapping of medial thalamic cells was performed and the final recording sites were stained by iontophoretic injection of pontamine blue (1.5 PA cathodal current applied during 30 min). The brains were sliced (50 pm) and sections were observed after Nissl staining. The electrode tracks were then reconstructed using microdrive reference points. During the entire experiment, heart rate was monitored continuously and body temperature maintained at about 37 “C by a hot water circulating pad. The first KC1 application was performed while recording from 2 cortical cells separated longitudinally by 5 mm. The distance between the cortical recording electrodes and the time difference between the appearance of CSD effects for each cortical cell were used to determine the speed of CSD propagation along the cortical surface (Fig. I). This manoeuvre was performed systematically. After this, one electrode was moved to record the thalamic activity and the other was left in place to record the cortical activity and to ensure the presence of CSD. Thalamic and cortical unit activity were recorded simultaneously using 2 separate amphfication channels. Each one permitted simultaneous recording of DC phenomena and spike activity.
T‘hu\. we could obser\:e the blockage of cortical rlruronal activity and also the DC changes accompanying CSD. Thalamic recordings allowed us to observe the cell responses to noxious stimulation and the effects of CSD upon these. The DC records from thalamic recording sites were made to ensure that the CSD did not propagate to subcortical structures. We tested the responses of thalamic and cortical cells to noxious heat stimulation that consisted of immersjng the tail in water at 50 *C for 40 sec. Also, responses to water at 30” C and to tactile stimulation were sought. Unit activities were digitalized and counted. These counts were plotted automatically by frequency: impulses per second fi.p.s.). DC levels were plotted on a pen recorder. Only thalamic cells which had a tail receptive field and responded to noxious stimulation were studied during the production of repeated CSDs. ln these situations, KC1 applications were separated by at least 20 min between tests. A maximum of 10 KC1 applications was employed in each animal. Results were not considered when epileptic discharges or multiple CSDs were produced by single KC1 application. Noxious stimulation was delivered with at least 20 min elapsing between tests and CL cell responses were studied during the propagation of the CSD along the cortical surface. The 20 min inter-trial periods between either KC1 applications or noxious stimulations were intended to reduce possible accumulative effects, multiple CSDs, or receptor adaptation processes. The 20 min intertrial periods required us to record a unit’s activity for periods longer than 60 min in order to make a complete test for CSD effects.
Results The mean speed of propagation of CSD was 4.9 mm/min i 1 mm. We confirmed that under urethane the CSD produced a reversible and transient suppression of cortical cell activities (Fig. 1). During simultaneous cortical and thalamic recording, a total of 112 thalamic cells were studied: 43 of these exhibited a response to noxious stimulation. We were able to test the effects of the
201
I
-b------
l
l
l ***
l
em
ALL.r,
I
I 20
Cx IOA
mV
uI
20
i.p.s.
I 20 i.p.s.
t-l
lmin
I min
Fig. 2. Frequency per second of CL cell activity during somatic stimulation of the tail. A shows the activations produced by tapping (0); B displays the effects of tail immersion in water at 30’ C; and C shows the activity during tail immersion in water at 50°C. The lower traces in B and C are for the stimulus signal, applied during the dense line.
Fig. 1. Simultaneous recordings of cortical activity during the effects of propagated CSD. Cortical cells were located at A 5.0 (Cx 5A) and A 10.0 (Cx 10A). The first and third traces are the DC levels and the second and fourth traces are impulses per second of the activity of a single unit. The propagated CSD affected the cell located at A 5.0 before affecting the cell at A 10.0. The time elapsing between the effects at each electrode and the distance between them were used to determine the speed of propagation. Note the initial high frequency discharge and the silence in both cells corresponding to the change in DC potential when they were affected in a transitory and reversible way. f KC1 J, time of cortical KC1 application.
with noxious stimulation (e.g., Fig. 2). This type of cell showed the highest discharge frequency to noxious stimulation. We also found CL cefls which responded only to noxious stimuli (9 of 43 cells; 21%). The spontaneous activity of both types of cells exhibited a low firing rate (O-5 i.p.s.) and displayed long periods of silence. The simultaneous recording of cortical and thalamic cells allowed us to observe that 9 cortical
cortical blockage by CSD on the responses to noxious stimulation in only 26 cells. Several cells (34 of 43 cells; 79%) responded to tactile stimulation and this response was enhanced
A
c’A St -
c
B
IL” _ &
tKCI
_ ,,,
, ,
&IIpOi.p.s.
I min Fig. 3. Simultaneous recording of cortical (Cx) and CL cell activities during noxious stimulation (A-C) and blockage of this response (in B) when CSD affected the corresponding cortical region. The cortical records were made at A 8.5. The first and third traces in each column are the cortical and thalamic DC levels, respectively; the second and fourth are frequency histograms of cell activities; the fifth trace is the stimulus signal, tail immersion in water at 50 o C during the dense line (St). In this particular case, the noxious stimulation in C was delivered 5 min after the stimulus in B (see Methods),
donates for each level. The thalamic cells responding to noxious stimulation were located mainly m the dorsal part of the CL thalamic nucleus (F’ig. 5 ). The cortical cells responding to noxious stimulation are shown in Fig. 6.
Discussion
4-
5
.A
I20
i.p.8.
I min Fig. 4. Relationship between cortical DC levels during CSD and i.p.s. of CL cell responses to noxious stimulation. In A, 5 superimposed traces of the cortical DC level during successive CSDa are shown. Twenty minute intervals were allowed between each KC1 application. The noxious stimulation was delivered at different times during the DC evolution (lower traces in 1, 2, 3. 4, and 5). Note that the blockage of the cell’s response in 3 coincides with the peak DC cortical level.
cells responded to noxious stimulation and these were located between A 8.2 and A 8.5; L 1.5 + 0.2; and at a depth of 1147 + 300 pm. When these cortical cells were blocked by CSD the noxious responses previously exhibited by the thalamic cells disappeared (Fig. 3). Thalamic DC records never showed great variations during the cortical propagation of the CSD, thus the effects on thalamic unit responses are not due to a transmission of CSD to the thalamus. Fig. 4 illustrates the blockage of thalamic responses when the CSD arrived at the medial frontal cortex. The blockage of the thalamic unit’s responses is well correlated with the peak of the DC level changes produced by CSD. Histological observations of brain sections and reconstruction of electrode tracts allowed us to construct a schematic representation of the thalamic and cortical cells from which we recorded. These locations were plotted on drawings of brain sections showing the stereotaxic coor-
The major findings of this study were that: (1) the study of cortico-thalamic relationships is possible using the CSD technique in urethane anaesthetized rats: (2) cells located in the prefrontal cortex as well as cells located in the dorsal portion of the CL responded to noxious stimulation; (3) the prefrontal cortex exerted a facilitatory tonic control upon the thalamic cells that was removed by CSD; and (4) the transient blockage of the prefrontal cortex by CSD caused a reversible suppression of the CL cell’s evoked responses to noxious stimulation. It has been demonstrated that the use of KC1 for transient suppression of neuronal activity is a good method for observing the cortico-thalamic relationships [4,12,24]. In the present paper. using rats under urethane, the speed of propagation, the blockage duration of cell activity and the general characteristics of the CSD were similar to those described in previous work [4,10,20,21]. The application of KC1 at the posterior cortex (A + 1) and the recording of cortical activity at prefrontal levels allowed us to observe the effects of a propagated CSD. However, the mechanisms of the propagation of CSD are presently obscure; they have been reviewed by BureS et al. [lo]. The relationships between the prefrontal medial cortex and the medial thalamic nuclei have been well established [2,19], and the presence of neuronal responses to noxious stimulation at this thalamic level, as is shown in this paper, is in agreement with the findings of other authors [1,4,11,13,22,23]. In our results, the presence of cortical cells responding to noxious stimulation in the prefrontal medial cortex suggests a cortical participation in pain transmission. It has been demonstrated [6,16,17] that electrical stimulation of this cortical area (the prefrontal cortex) produces a significant
203
z# NOXIOUS A
THERMAL
NON - RESPONSIVE
RESPONSIVE
CELLS
CELLS
A 5.6
A4,4 Fig. 5. Schematic ~~~st~~ti~~ of the Iocatians of medial thalamic c&s from which recrrrdings were made. Diagrams are taken from a stereotaxic atlas [3]. Note the con~ntra~~~ of cells with noxious responses in the dorsal portion of the CL nucleus. Not all the recorded ceils were plotted because of cell superimpositicm, Each point may represent a few cells.
reduction of nociceptive responses. These authors conclude that spinal and supraspinal mechanisms are involved in pain control and also suggest a mechanism of cortical control over pain perception. It is interesting that electrical stimulation of
Fig. 6. Location of cortical cells responding to noxious stimulation. Schematic reconstruction and diagrams are as in Fig. 5.
the prefrontal cortex [S] and the selective suppression of the same cortical area by means of CSD causes - in both cases - the blockage of nociceptive evoked responses in medial thalamic cells. In our present findings, the cortical action upon the transmission of nociceptive information could be explained by a cortical action at thaIan& level. Moreover, our results suggest a cortico-thalamic control of pain transmission. The intracellular study of Andersen [6] proposes that the suppression of medial thalarnic noxious responses by cortical stimulation is due to h~pe~ola~atiou of the thalamic cells. In our study we did not make intracellular penetrations, but the extracellular DC records from the medial thalamic cell recording loci do not show great variations. However, further intracellular records are necessary to clarify this point.
204
Acknowledgement This work was partially supported by a cesearch grant from Consejo National de C‘iencia y Tecnologia CONACyT (PCEXCNA 040661).
! I C‘;wy. K.L., Cnit analyGs of nociccptive rnechanwn~ 111 the thalamus of the awake squirrel monkev. J. Nwroph\h loI.. 29 C1966) 127 750. I7 (‘ondka-Lara. M.. Kesar. S. and ‘Alhe-Frsharcl. If., <‘onpnrison of caudate nucleus and huhstantia nipra contr(>l rlf medial thalamtc cell activitle?, in the rat. Neuro\cl. I.ctt . II (19X2)12) 134. I?
References 1 Albe-Fessard, D. and Kruger, L., Duality of unit discharges from cat centrum medianum in response to natural and electrical stimulation, J. Neurophysiol., 25 (1962) 3-20. 2 Albe-Fessard, D., Levante, A. and Rokyta. R., Cortical projections of cat medial thalamic cells. lnt. J. Neurosci.. 1 (1971) 327-338. 3 Albe-Fessard, D.. Stutinsky, F. et Libouban. S.. Atlas StCrCotaxique du DiencCphale du Rat Blanc. Editions du C.N.R.S., Paris, 1971, 46 pp. 4 Albe-Fessard. D.. Cond&Lara. M., Kesar. S. and Sanderson, P.. Tonic cortical controls acting on spontaneous and evoked thalamic activity. In: G. Macchi. A. Rustioni and R. Spreafico (Eds.). Progress in Brain Research. Somatosensory Integration in the Thalamus, Elsevier Science Publishers, Amsterdam. 1983, pp. 273-285. D.. Berkley, K.J.. Kruger. L.. Ralston, III. 5 Albe-Fessard. H.J. and Willis, Jr., W.D., Diencephalic mechanisms of pain sensation, Brain Res. Rev.. 9 (1985) 217-296. 6 Andersen, E., Periaqueductal gray and cerebral cortex modulate responses of medial thalamic neurons to noxious stimulation, Brain Res., 375 (1986) 30-36. E. and Dafny, N.. Dorsal raphe stimulation I Andersen. reduces responses of parafascicular neurons to noxious stimulation, Pain, 15 (1983) 323-331. facilir Anderson, P.. Junge, K. and Sveen, 0.. Cortico-fugal tation of thalamic transmission. Brain Behav. Evolut.. 6 (1972) 170&184. neurons of the 9 Azmitia. EC., ‘The serotonine-producing midbrain-medial and dorsal raphe nuclei. In: L.I. Eversen (Ed.), Handbook of Psychopharmacology, Vol. 9. Plenum Press, New York, 1981, pp. 233-314. 10 BureS, J.. BureSova. 0. and KiivBnek. J., The Mechanism and Applications of L&o’s Spreading Depression of Electroencephalographic Activity, Academia Praha. Prague, 1974.410 pp.
14
15
I6 17
1x
19 20 21 22
23
Dong. W.K.. Ryu, H and Wagman. I.H.. Noclceptlve wponses of neurons in medial thalamus and their relationihip to spmothalamic pathways. J. Neurophyswl 41 (197X) 15Y2- 1613. I:cltz. P.. Krauthamer. C;. and Albe-Fesaard. I).. Neuron\ nf the medial diencephalon. 1. Somatosensory respomeh .md caudate inhibition, J. Neurophysiol., 30 (1967) 55--X& Hagbarth. K.E. and Keer. D.I.B.. Central mfluences on spinal afferent conduction. J. Neurophysml.. 17 C1954) 295-307. Hardy. S.G.P., Analgesia elicited by prefrontal stlmulatlon. Brain Res.. 239 (1985) 281--2X4. Hardy, S.G.P. and Haigler. H.J.. Prefrontal influences upon the midbrain: a possible route for pain modulation, Brain Res., 339 (1985) 285.. 293. Ishlda. Y. and Kitano. K., Raphe Induced inhihitmn of lntralammar thalamic unitary activities and its blockade by p~~rrtl-chlorophenylalanine in cats, Naunyn-Schmiedeberg’h Arch. Pharmacol.. 301 (1977) 1-- 4. Jones. E.G.. The Thalamus. Plenum Press, New York. lY85. 435 pp. Le%o. A.A.P.. Spreading depression of activity in thr cerebral cortex, J. Neurophysiol., 7 (1944) 359-390. L&o. A.A.P. and Morrison, R.S., Propagation of spreading cortical depression. J. Neurophyslol., 8 (1945) ?3-~45. Nyquist, J.K. and Greenhoot. J.H.. Responses evoked from the thalamic ccntrum medianum by painful input: supprea\lon hy dorsal funiculua conditioning, Exp. N’eurol.. 3Y (1973) 21s -222. Peschanski, M., Guilbaud, G. and Gautron, M., Postenor Intralaminar nuclei in the rat-neurons responses to noxious and non-noxious cutaneous stimuli, Exp. Neural.. 72 (1981)
226-238. thalamic 24 Wailer. H.J. and Feldman. SM., Somatosensory neurons: effects of cortical depression, Science. 157 ( 1967) 1074- 1077. T.J. and Casey, K.L., Corttcofugal 25 Yuan. B., Morrow. influences of Sl cortex on ventrobasal thalamic neurons in the awake rat. J. Neurosci., 6 (1986) 3611-3617
Pain, 35 (1988) 199-204 Elsevier
PA1 01296
Suppression of noxious thermal evoked responses in thalamic central lateral nucleus by cortical spreading depression Miguel CondCs-Lara
* and Imelda Omaha Zapata
**
* Departamento
de Neurofisiologia, Diuisibn de Investigaciones en Neurociencias. Institute Mexicano de Psiquiatria, Calzada M&co-Xochimilco 101, Mexico, D.F. 14370 (Mexico), and * * Coordinacibn de Estudios de Postgrado, Inuestigaci6n y Desarrollo Acadbnico ENEP, Zaragora, UNA M, Mexico (Mexico) (Received
17 February
1988, revision received 9 May 1988, accepted
15 June 1988)
s-w
Several thalamic nuclei are associated with the processing of pain information and are influenced by’cortical actions. This paper demonstrates a cortical influence upon the medial thalamic nuclei unit activity evoked by thermal noxious stimulation in rats. We studied the effects of cortical spreading depression (CSD) upon the responses of the centralis lateralis (CL) nucleus of the medial thalamus to noxious heat stimulation. Urethane was used as anaesthetic. Cells responding to noxious stimulation were localized in the dorsal portion of the CL. These cells responded like polymodal or nociceptive specific units in the spinal cord and exhibited their highest discharge frequency with noxious stimuli. When CSD is propagated and affects the medial frontal cortex it blocks the responses evoked in CL cells by noxious stimulation. Cortical cells located at this level also exhibited responses evoked by noxious stimulation. Our results suggest a cortical facilitatory control upon the noxious responses recorded in the CL cells. Key words:
Thalamic
nuclei;
Noxious
thermal
evoked
responses;
Introduction Cells located in the medial thalamus (parafascicentralis medialis, centralis lateralis, cularis, centrum medianum nuclei) respond to noxious peripheral stimulation in the rat [7,23], cat [1,14,18,22] and monkey [ll]. The role of these neurons in processing pain information was recently reviewed [5]. It is claimed [6,7] that the medial thalamic cells are under the control of an ascending pain modulation system producing
Cortical
influence;
Rats
analgesia. This could originate with the projection from neurons located within the periaqueductal gray of the midbrain containing serotonin, a neurotransmitter known to be involved in analgesia
[91. The cerebral cortex (Cx) has also been shown to play a role in pain modulation [6,15-171. It has been shown to exert a facilitatory action over medial thalamic cells [4,8,12,24,25]; however, electrical stimulation of the cortex suppresses the re; sponses of medial thalamic cells to noxious stimuli
[61.
Correspondence to: Dr. Miguel Condts-Lara, Departamento de Neurofisiologia, Divisi6n de Investigaciones en Neurociencias, Instituto Mexican0 de Psiquiatria, Calzada MtxicoXochimilco 101. Mexico, D.F. 14370, Mexico. 0304-3959/88/$03.50
The present study explored further the role of the cerebral cortex in the modulation of responses to noxious stimuli in the medial thalamus. For this we used a transient and reversible blockage of cortical activity by means of the cortical spreading depression technique [10,20,21].
0 1988 Elsevier Science Publishers B.V. (Biomedical Division)
Xi! Methods Twenty-two male albino rats (Wistar) weighing 250-300 g were used. Subjects were anaesthetized with urethane (1500-2~ mg/kg i.p.) and placed in a stereotaxic apparatus. The stereotaxic coordinates and the incisor bar orientation were those used by Albe-Fessard et al. [3]. The head was shaved and the skull exposed. Two holes were drilled into the bone. One, at A 1.0 and L 2.0, was used for the application (of 60 set duratjon) of small pieces of paper (1 mm2) soaked in a KC1 solution (1 M) to produce cortical spreading depression (CSD). The other, made between A 4.5 and 10.5, and L 0.5-2.5, allowed us to place the electrodes for recording unit activity. We studied cells located in the cerebral cortex (Cx) and in the nuclei centralis lateralis (CL), ventralis lateralis (VL) and lateralis (L) of the thalamus. Single units were recorded using glass micropipettes filled with a 4R solution of pontamine blue in 1 M KC1 (impedance 8-10 MO). A systematic mapping of medial thalamic cells was performed and the final recording sites were stained by iontophoretic injection of pontamine blue (1.5 PA cathodal current applied during 30 min). The brains were sliced (50 pm) and sections were observed after Nissl staining. The electrode tracks were then reconstructed using microdrive reference points. During the entire experiment, heart rate was monitored continuously and body temperature maintained at about 37 “C by a hot water circulating pad. The first KC1 application was performed while recording from 2 cortical cells separated longitudinally by 5 mm. The distance between the cortical recording electrodes and the time difference between the appearance of CSD effects for each cortical cell were used to determine the speed of CSD propagation along the cortical surface (Fig. I). This manoeuvre was performed systematically. After this, one electrode was moved to record the thalamic activity and the other was left in place to record the cortical activity and to ensure the presence of CSD. Thalamic and cortical unit activity were recorded simultaneously using 2 separate amphfication channels. Each one permitted simultaneous recording of DC phenomena and spike activity.
T‘hu\. we could obser\:e the blockage of cortical rlruronal activity and also the DC changes accompanying CSD. Thalamic recordings allowed us to observe the cell responses to noxious stimulation and the effects of CSD upon these. The DC records from thalamic recording sites were made to ensure that the CSD did not propagate to subcortical structures. We tested the responses of thalamic and cortical cells to noxious heat stimulation that consisted of immersjng the tail in water at 50 *C for 40 sec. Also, responses to water at 30” C and to tactile stimulation were sought. Unit activities were digitalized and counted. These counts were plotted automatically by frequency: impulses per second fi.p.s.). DC levels were plotted on a pen recorder. Only thalamic cells which had a tail receptive field and responded to noxious stimulation were studied during the production of repeated CSDs. ln these situations, KC1 applications were separated by at least 20 min between tests. A maximum of 10 KC1 applications was employed in each animal. Results were not considered when epileptic discharges or multiple CSDs were produced by single KC1 application. Noxious stimulation was delivered with at least 20 min elapsing between tests and CL cell responses were studied during the propagation of the CSD along the cortical surface. The 20 min inter-trial periods between either KC1 applications or noxious stimulations were intended to reduce possible accumulative effects, multiple CSDs, or receptor adaptation processes. The 20 min intertrial periods required us to record a unit’s activity for periods longer than 60 min in order to make a complete test for CSD effects.
Results The mean speed of propagation of CSD was 4.9 mm/min i 1 mm. We confirmed that under urethane the CSD produced a reversible and transient suppression of cortical cell activities (Fig. 1). During simultaneous cortical and thalamic recording, a total of 112 thalamic cells were studied: 43 of these exhibited a response to noxious stimulation. We were able to test the effects of the
201
I
-b------
l
l
l ***
l
em
ALL.r,
I
I 20
Cx IOA
mV
uI
20
i.p.s.
I 20 i.p.s.
t-l
lmin
I min
Fig. 2. Frequency per second of CL cell activity during somatic stimulation of the tail. A shows the activations produced by tapping (0); B displays the effects of tail immersion in water at 30’ C; and C shows the activity during tail immersion in water at 50°C. The lower traces in B and C are for the stimulus signal, applied during the dense line.
Fig. 1. Simultaneous recordings of cortical activity during the effects of propagated CSD. Cortical cells were located at A 5.0 (Cx 5A) and A 10.0 (Cx 10A). The first and third traces are the DC levels and the second and fourth traces are impulses per second of the activity of a single unit. The propagated CSD affected the cell located at A 5.0 before affecting the cell at A 10.0. The time elapsing between the effects at each electrode and the distance between them were used to determine the speed of propagation. Note the initial high frequency discharge and the silence in both cells corresponding to the change in DC potential when they were affected in a transitory and reversible way. f KC1 J, time of cortical KC1 application.
with noxious stimulation (e.g., Fig. 2). This type of cell showed the highest discharge frequency to noxious stimulation. We also found CL cefls which responded only to noxious stimuli (9 of 43 cells; 21%). The spontaneous activity of both types of cells exhibited a low firing rate (O-5 i.p.s.) and displayed long periods of silence. The simultaneous recording of cortical and thalamic cells allowed us to observe that 9 cortical
cortical blockage by CSD on the responses to noxious stimulation in only 26 cells. Several cells (34 of 43 cells; 79%) responded to tactile stimulation and this response was enhanced
A
c’A St -
c
B
IL” _ &
tKCI
_ ,,,
, ,
&IIpOi.p.s.
I min Fig. 3. Simultaneous recording of cortical (Cx) and CL cell activities during noxious stimulation (A-C) and blockage of this response (in B) when CSD affected the corresponding cortical region. The cortical records were made at A 8.5. The first and third traces in each column are the cortical and thalamic DC levels, respectively; the second and fourth are frequency histograms of cell activities; the fifth trace is the stimulus signal, tail immersion in water at 50 o C during the dense line (St). In this particular case, the noxious stimulation in C was delivered 5 min after the stimulus in B (see Methods),
donates for each level. The thalamic cells responding to noxious stimulation were located mainly m the dorsal part of the CL thalamic nucleus (F’ig. 5 ). The cortical cells responding to noxious stimulation are shown in Fig. 6.
Discussion
4-
5
.A
I20
i.p.8.
I min Fig. 4. Relationship between cortical DC levels during CSD and i.p.s. of CL cell responses to noxious stimulation. In A, 5 superimposed traces of the cortical DC level during successive CSDa are shown. Twenty minute intervals were allowed between each KC1 application. The noxious stimulation was delivered at different times during the DC evolution (lower traces in 1, 2, 3. 4, and 5). Note that the blockage of the cell’s response in 3 coincides with the peak DC cortical level.
cells responded to noxious stimulation and these were located between A 8.2 and A 8.5; L 1.5 + 0.2; and at a depth of 1147 + 300 pm. When these cortical cells were blocked by CSD the noxious responses previously exhibited by the thalamic cells disappeared (Fig. 3). Thalamic DC records never showed great variations during the cortical propagation of the CSD, thus the effects on thalamic unit responses are not due to a transmission of CSD to the thalamus. Fig. 4 illustrates the blockage of thalamic responses when the CSD arrived at the medial frontal cortex. The blockage of the thalamic unit’s responses is well correlated with the peak of the DC level changes produced by CSD. Histological observations of brain sections and reconstruction of electrode tracts allowed us to construct a schematic representation of the thalamic and cortical cells from which we recorded. These locations were plotted on drawings of brain sections showing the stereotaxic coor-
The major findings of this study were that: (1) the study of cortico-thalamic relationships is possible using the CSD technique in urethane anaesthetized rats: (2) cells located in the prefrontal cortex as well as cells located in the dorsal portion of the CL responded to noxious stimulation; (3) the prefrontal cortex exerted a facilitatory tonic control upon the thalamic cells that was removed by CSD; and (4) the transient blockage of the prefrontal cortex by CSD caused a reversible suppression of the CL cell’s evoked responses to noxious stimulation. It has been demonstrated that the use of KC1 for transient suppression of neuronal activity is a good method for observing the cortico-thalamic relationships [4,12,24]. In the present paper. using rats under urethane, the speed of propagation, the blockage duration of cell activity and the general characteristics of the CSD were similar to those described in previous work [4,10,20,21]. The application of KC1 at the posterior cortex (A + 1) and the recording of cortical activity at prefrontal levels allowed us to observe the effects of a propagated CSD. However, the mechanisms of the propagation of CSD are presently obscure; they have been reviewed by BureS et al. [lo]. The relationships between the prefrontal medial cortex and the medial thalamic nuclei have been well established [2,19], and the presence of neuronal responses to noxious stimulation at this thalamic level, as is shown in this paper, is in agreement with the findings of other authors [1,4,11,13,22,23]. In our results, the presence of cortical cells responding to noxious stimulation in the prefrontal medial cortex suggests a cortical participation in pain transmission. It has been demonstrated [6,16,17] that electrical stimulation of this cortical area (the prefrontal cortex) produces a significant
203
z# NOXIOUS A
THERMAL
NON - RESPONSIVE
RESPONSIVE
CELLS
CELLS
A 5.6
A4,4 Fig. 5. Schematic ~~~st~~ti~~ of the Iocatians of medial thalamic c&s from which recrrrdings were made. Diagrams are taken from a stereotaxic atlas [3]. Note the con~ntra~~~ of cells with noxious responses in the dorsal portion of the CL nucleus. Not all the recorded ceils were plotted because of cell superimpositicm, Each point may represent a few cells.
reduction of nociceptive responses. These authors conclude that spinal and supraspinal mechanisms are involved in pain control and also suggest a mechanism of cortical control over pain perception. It is interesting that electrical stimulation of
Fig. 6. Location of cortical cells responding to noxious stimulation. Schematic reconstruction and diagrams are as in Fig. 5.
the prefrontal cortex [S] and the selective suppression of the same cortical area by means of CSD causes - in both cases - the blockage of nociceptive evoked responses in medial thalamic cells. In our present findings, the cortical action upon the transmission of nociceptive information could be explained by a cortical action at thaIan& level. Moreover, our results suggest a cortico-thalamic control of pain transmission. The intracellular study of Andersen [6] proposes that the suppression of medial thalarnic noxious responses by cortical stimulation is due to h~pe~ola~atiou of the thalamic cells. In our study we did not make intracellular penetrations, but the extracellular DC records from the medial thalamic cell recording loci do not show great variations. However, further intracellular records are necessary to clarify this point.
204
Acknowledgement This work was partially supported by a cesearch grant from Consejo National de C‘iencia y Tecnologia CONACyT (PCEXCNA 040661).
! I C‘;wy. K.L., Cnit analyGs of nociccptive rnechanwn~ 111 the thalamus of the awake squirrel monkev. J. Nwroph\h loI.. 29 C1966) 127 750. I7 (‘ondka-Lara. M.. Kesar. S. and ‘Alhe-Frsharcl. If., <‘onpnrison of caudate nucleus and huhstantia nipra contr(>l rlf medial thalamtc cell activitle?, in the rat. Neuro\cl. I.ctt . II (19X2)12) 134. I?
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