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Evidence for involvement of the frontal cortex in pain-related cerebral events in cats: increase in local cerebral blood flow by noxious stimuli
Brain Research, 217 (1981) 179-185 © Elsevier/North-Holland Biomedical Press
179
Evidence for involvement of the frontal cortex in pain-related cerebral events in cats: increase in local cerebral blood flow by noxious stimuli
T. TSUBOKAWA, Y. KATAYAMA, Y. UENO and N. MORIYASU Neurophysiological Laboratory, Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173 (Japan)
(Accepted March 12th, 1981) Key words: catecholaminergic system - - frontal cortex - - local cerebral blood flow - - pain
Noxious stimuli were shown to induce a remarkable increase in local cerebral blood flow restricted to the forepart of the cerebral hemispheres bilaterally anterior to the posterior sigmoid gyrus in cats. This increase in local cerebral blood flow was averted by lesions in the bilateral ventromedial thalamus and attenuated by pretreatment with an intraventricular injection of 6-hydroxydopamine. Pain is a purely subjective phenomenon. When studying pain in animals, therefore, the question arises as to whether pain that is equivalent to pain for man also exists in animals. The behavior of animals subjected to noxious stimuli is too stereotyped to suppose any important role played by the cerebral cortex in the pain mechanism. Little is yet known in this regard, presumably because of the complexity of cortical function, which does not demonstrate any simple neuronal response to the noxious stimuli. Recently, a spatial correlation between neuronal activities and local cerebral blood flow (L-CBF) has been reportedS,11,14,1~. This is interpreted as evidence for metabolic regulation of L-CBF reflecting the activity level and oxygen demand of neurons la. Conversely, the activity level of neurons might be said to be in change when changes in L-CBF are observed under physiological conditions. F r o m this viewpoint, measurements of L-CBF by the hydrogen clearance method 1 offer the advantage of revealing the average activity level of the neuronal pool in a given column of radius 600-800/~m 15. The present experiments were designed using this technique to detect the cortical areas activated by receiving noxious stimuli in cats. Experiments were carried out on 22 adult cats. Four of the animals received an injection of 6-hydroxydopamine (6-OHDA) (400-500 #g) into the lateral ventricle at least 6 days before the experiment. Fluorescence histochemistry demonstrated a marked overall reduction of the central noradrenaline nerve terminals in cats pretreated with 6-OHDA15. The animals were initially anesthetized with pentobarbital sodium (30 mg/kg, i.m.) for surgical manipulation, paralyzed with gaUamine triethiodide and ventilated artificially so that the arterial p H and gas tensions were within physiological limits. A total of 6 small holes were made in the skull to permit the
180 insertion of electrodes into the frontal, parietal and occipital areas bilaterally. A teflon-coated platinum filament, 200 # m in diameter, with a 1.0 m m portion at its tip uncoated and plated with platinum black served as the electrode, and was inserted 1.0 m m from the cortical bank. Exposed cortical surface was thickly covered with tyrode agar. Systematic exploration of each area was carried out to determine the changes in various gyri. The left sciatic nerve was exposed at the popliteal level. After completion of surgery, the animals were rested without recording until the corneal reflex reappeared with reduction of the effects of the initially administered pentobarbital. Wound margins and pressure points were treated minutely by infiltration of xylocaine hydrochloride, which was readministered periodically during the experiment. Attention was payed throughout the experiment on the pupils, as an index of painless state, which were smaller than medium size in diameter except when the animals were subjected to the external stimuli. All of the experimental procedures was carefully arranged to confine the external stimuli to the minimum necessity. The situation with (1) repetitive electrical stimulation of the sciatic nerve with an intensity 10 ~o above the thresholds activating A6 and C fibers (usually over 125 mA; pulse duration, 0.5 msec) at 10-100 Hz; or (2) perfusion of bradykinin (25 #g/ml in 0.9% sodium chloride solution) into the right lower extremity (25 /zg), was studied. Each animal was subjected twice to sciatic stimulation with different cycles and twice to bradykinin perfusion with sufficient intervals. These procedures were completed within 1.5 h from the time of the reappearance of the corneal reflex and immediately followed by an administration of an overdose of pentobarbital. In 3 animals, minimum necessary period of repetitive sciatic nerve stimulation to induce noticeable changes in L-CBF was assessed and it was shown that a period of 30 sec was required. Based on this result, only the effects of stimulation with a period of 30 sec were investigated in remaining cats. Each animal was made to inhale 5 ~ hydrogen gas for 30 sec starting 1 min after the onset of electrical stimulation or bradykinin perfusion. In 8 animals, the effects of electrolytic destruction of the ventromedial, ventrolateral or dorsal
TABLE I Changes of I-CBF in the gyrus proreus induced by repetitive stimulation of the left sciatic nerve with noxious intensity
Values were obtained from 10 different cats. Stim. ( Hz)
Control 10 20 40 60 100 * P <: 0.05.
l-CBF in gyrus proreus ( ml/ l O0 g /min ) Right
Left
44.0 :~ 6.4 64.6 ± 6.1" 60.7 ± 6.4* 51.3 ± 4.9 50.9 i 6.2 50.4 ± 5.3
45.1 ± 5.9 65.7 ± 6.8* 61.0 ± 6.4* 50.9 :j__5.1 49.9 ± 5.6 49.8 ± 5.2
181 TABLE II
Changes in the averaged CBF of various cortical areas induced by bradykinin perfusion into the right lower extremity CBF (ml/lO0 g/min)
Lt-frontal area* Rt-frontal area* Lt-parietal area Lt-occipital area
Control
Bradykinin perfusion
42.5 44.6 51.7 42.2
83.2 88.1 60.7 48.0
:E 7.1 :E 5.4 :E 6.6 :E 4.2
4- 19.2"* -4- 14.9"* :E 11.3"** ± 8.5
* Including the posterior sigmoid gyrus. ** P < 0.005. *** P < 0.05.
H2 CL CURVI
I0 mV
CBF
IO W TEMP.
0.5
°C
SBP I00 5O BRADYKININ
I
I
I min Fig. 1. Example of the time course of CBF in the frontal area, systemic arterial pressure, and heart rate. CBF was measured by the thermoelectric technique.
182 TABLE III Effects o f pretreatment by an intraventricular injection o f 6-OHDA (400-500 #g) on the CBF increase in the frontal area induced by bradykinin perfusion into the lower extremity CBF in left frontal area (ml/lO0 g/min)
Untreated 6-OHDApretreated
Control
Bradykinin perfusion
42.5 i 7.1 52.3 _-k_7.8
83.2 ± 19.2" 66.8 ± 15.1"*
* P < 0.005. ** P < 0.05. thalamus on changes in L-CBF induced by noxious stimuli were studied. The surgical and recording procedures were as described in detail elsewherO
183
175
,'9.5
Fig. 2. Diagrammatic view of the coronal sections indicating ventromedial thalamic lesion which was made bilaterally and shown to avert induction of a CBF increase in the frontal area by noxious stimuli. CL, central lateral nucleus; CM, central medial nucleus; GL, lateral geniculate body; GM, medial geniculate body; HL, lateral habenular nucleus; LD, lateral dorsal nucleus; LP, lateral posterior nucleus; MD, medial dorsal nucleus; MM, medial mammillary nucleus; NCM, center median nucleus; PC, paracentral nucleus; PP, pes pedunculi.
Bilateral ventromedial thalamic lesions, including the greater part of the center median nucleus, the parafascicular nucleus, and habenulointerpeduncular tract, the caudal lower part of the dorsal medial nucleus, part of the nucleus of the posterior commissure, the nucleus limitans, and the central gray (Fig. 2), seriously suppressed the CBF increase in the frontal area. The CBF values increased only from 40.8 -I- 6.3 to 48.6 ± 8.6 ml/100 g/min, i.e. a 19 ~ increase from the resting value (Table IV). This difference was not statistically significant. On the other hand, bilateral ventrolateral thalamic lesions, including the greater part of the ventral posterolateral nucleus, fields of Forel, and ventral posteromedial nucleus, showed almost no effect. Bilateral dorsal thalamic lesions, which involved the greater part of the medial dorsal nucleus, medial half of the lateral medial nucleus, upper half of the center median nucleus, medial part TABLE IV
Effects of various thalamic lesions on the CBF increase in the left frontal area induced by bradykinin perfusion into the right lower extremity Thalamic lesion
Dorsal thalamus Ventrolateral thalamus Ventromedial thalamus * P < 0.05. ** NS.
CBF in left frontal area (ml/lO0 g/min) Control
Bradykinin perfusion
42.0 i 5.3 54.3 ± 8.6 40.8 ± 6.3
74.7 4- 9.2* 103.9 -k 16.4" 48.6 q- 8.6**
184 of the central lateral nucleus and the habenular nucleus, also revealed no significant effect. The CBF in the frontal area increased from 42.0 ± 5.3 to 74.7 ± 9.2 ml/100 g/min, i.e. a 79 ~ increase from the resting value, in spite of receiving the bilateral dorsal thalamic lesions. The first point which should be considered in relation to these results is whether the CBF increases are not produced by a raised systemic arterial pressure or heart rate. Raised arterial pressure and heart rate are thought to be manifestations of subjective pain experience. The different time courses of the CBF increase and raised arterial pressure or heart rate may provide an answer to this question (Fig. 1). The difference in time course may be well interpreted as the time lag to induce a CBF increase by raised neuronal activity. It has been reported that a time lag of over 1 min exists between acceleration of cerebral metabolism resulting from raised neuronal activity and increase of the CBF 11. This observation could therefore represent indirect evidence favoring the CBF increase resulting from acceleration of the cerebral metabolism in the frontal area related to pain experience. Naturally, a raised arterial pressure or heart rate does not reflect on a CBF increase restricted to the frontal area. While bilateral dorsal or ventrolateral thalamic lesions did not exert significant effect on the CBF increase in the frontal, bilateral ventromedial thalamic lesions averted it almost completely (Table IV). This suggests that CBF increases in the frontal area are intimately related to the activity of the subcortical pain pathwayT,lz, ~3. Although the non-specific reticular activating system activated by noxious stimuli might play a partial role, especially in diffuse CBF increases spread over the entire cerebral cortex 8, it can be concluded that increased activities of an appreciable population of neurons in the frontal cortex activated through the subcortical pain pathway might be related to a CBF increase restricted to the frontal area. CBF increase in the frontal area was significantly reduced by chemical denervation of the catecholaminergic system (Table III). Although further studies are required to determine the precise role of the catecholaminergic system, there appears to be some justification for considering that this finding may be related to at least two types of observations: (1) destruction of noradrenalin fibers has been shown to increase the pain threshold 3,~°, therefore, CBF increase in the frontal area related to pain may be reduced; and (2) destruction of noradrenalin fibers has been reported to exert a serious effect on the normal relationships between neuronal activity and CBF2,4,9,'4; thus, CBF increase may be impaired despite pain mechanism being preserved. These two possibilities appear to be interrelated when the idea that the catecholaminergic system may be involved in the cerebral oxidative metabolism in situ 6 is taken into consideration. Based on the present results and other available evidencO 4A5, it is concluded that the CBF increase in the frontal area induced by noxious stimuli provides possible evidence favoring involvement of the frontal cortex in pain-related cerebral events in the cat. This work was supported by a Japan Education Ministry Grant.
185 1 Aukland, K., Bower, B. F. and Berliner, R. W., Measurement of local blood flow with hydrogen gas, Circulat. Res., 14 (1964) 164--187. 2 Bates, D., Weinshilboum, R. M., Campbell, R. J. and Sundt, T. M. Jr., The effect of lesions in the locus coeruleus on the physiological responses of the cerebral blood vessels in cats, Brain Research, 136 (1977) 431-443. 3 Bodnar, R. J., Ackerman, R. F., Kelly, D. D. and Glusman, M., Elevations in nociceptive thresholds following locus coeruleus lesions, Brain Res. Bull., 3 (1978) 125-130. 4 Edvinsson, L., Hardebo, J. E. and MacKenzie, E. T., Effects of intraventricular 6-hydroxydopamine on cerebrovascular CO2 reactivity in anesthetized rats, Acta physioL scand., 101 (1977) 122-125. 5 Hand, P. J., Greenberg, J., Goochee, G., Sylvesno, A., Weller, L. and Reivich, M., A normal and developmentally altered cortical column. A laminar analysis of local glucose utilization with natural stimulation of a single receptor organ, Acta neurol, scand., Suppl. 72 (1979) 46--47. 6 Harik, S. I., LaManna, J. C., Light, A. I. and Rosenthal, M., Cerebral norepinephrine: influence on cortical oxidative metabolism in situ, Science, 206 (1979) 69-70. 7 Hassler, R., Dichotomy of facial pain conduction in the diencephalon. In R. Hassler and A. R. Walker (Eds.), Trigeminal Neuralgia, George Thieme, Stuttgard, 1970, pp. 121-138. 8 Ingvar, D. H., Extraneural influences upon the electrical activity of isolated cortex following stimulation of the reticular activating system, Acta physioL scand., 33 (1955) 169-193. 9 Mendelow, A. P., McCalden, T. A., Hattingh, J., Kramer, B., Rosendorff, C. and Eidelman, B. H., The effect of chemical sympathectomy on cerebrovascular reactivity and cerebral metabolism. In C. Owman and L. Edvinsson (Eds.), Neurogenic Control of Brain Circulation, Pergamon Press, Oxford, 1977, pp. 429-442. 10 Sasa, M., Munekiyo, K., Osuari, Y. and Takaoni, S., Attenuation of morphine analgesia in rats with lesions of the locus coeruleus and dorsal raphe nucleus, Europ. J. PharmacoL, 42 (1977) 53-62. 11 Sokoloff, L., Local cerebral energy metabolism, its relationships to local functional activity and blood flow. In Cerebral Vascular Smooth Muscle and Its Control, Ciba Foundation Symposium 56, Elsevier, Amsterdam, 1978, pp. 171-197. 12 Tsubokawa, T., The correlation of pain relief, neurological signs, EEG and anatomical lesion sites in pain patients treated by stereotaxic thalamotomy, Folia physchiat, neurol, jap., 21 (1967) 41-50. 13 Tsubokawa, T. and Moriyasu, N., Follow-up results of centre median thalamotomy for relief of intractable pain, Confin. neuroL (Basel), 37 (1975) 280-284. 14 Tsubokawa, T., Katayama, Y., Kondo, T., Veno, Y., Hayashi, N. and Moriyasu, N., Changes in local cerebral blood flow and neuronal activity during sensory stimulation in normal and sympathectomized cats, Brain Research, 190 (1980) 51-65. 15 Ueno, Y., Changes in local cerebral blood flow by afferent stimulation: The role of intracerebral monoaminergic system, Nihon Univ. J. Med., 39 (1980) 387-403.
179
Evidence for involvement of the frontal cortex in pain-related cerebral events in cats: increase in local cerebral blood flow by noxious stimuli
T. TSUBOKAWA, Y. KATAYAMA, Y. UENO and N. MORIYASU Neurophysiological Laboratory, Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173 (Japan)
(Accepted March 12th, 1981) Key words: catecholaminergic system - - frontal cortex - - local cerebral blood flow - - pain
Noxious stimuli were shown to induce a remarkable increase in local cerebral blood flow restricted to the forepart of the cerebral hemispheres bilaterally anterior to the posterior sigmoid gyrus in cats. This increase in local cerebral blood flow was averted by lesions in the bilateral ventromedial thalamus and attenuated by pretreatment with an intraventricular injection of 6-hydroxydopamine. Pain is a purely subjective phenomenon. When studying pain in animals, therefore, the question arises as to whether pain that is equivalent to pain for man also exists in animals. The behavior of animals subjected to noxious stimuli is too stereotyped to suppose any important role played by the cerebral cortex in the pain mechanism. Little is yet known in this regard, presumably because of the complexity of cortical function, which does not demonstrate any simple neuronal response to the noxious stimuli. Recently, a spatial correlation between neuronal activities and local cerebral blood flow (L-CBF) has been reportedS,11,14,1~. This is interpreted as evidence for metabolic regulation of L-CBF reflecting the activity level and oxygen demand of neurons la. Conversely, the activity level of neurons might be said to be in change when changes in L-CBF are observed under physiological conditions. F r o m this viewpoint, measurements of L-CBF by the hydrogen clearance method 1 offer the advantage of revealing the average activity level of the neuronal pool in a given column of radius 600-800/~m 15. The present experiments were designed using this technique to detect the cortical areas activated by receiving noxious stimuli in cats. Experiments were carried out on 22 adult cats. Four of the animals received an injection of 6-hydroxydopamine (6-OHDA) (400-500 #g) into the lateral ventricle at least 6 days before the experiment. Fluorescence histochemistry demonstrated a marked overall reduction of the central noradrenaline nerve terminals in cats pretreated with 6-OHDA15. The animals were initially anesthetized with pentobarbital sodium (30 mg/kg, i.m.) for surgical manipulation, paralyzed with gaUamine triethiodide and ventilated artificially so that the arterial p H and gas tensions were within physiological limits. A total of 6 small holes were made in the skull to permit the
180 insertion of electrodes into the frontal, parietal and occipital areas bilaterally. A teflon-coated platinum filament, 200 # m in diameter, with a 1.0 m m portion at its tip uncoated and plated with platinum black served as the electrode, and was inserted 1.0 m m from the cortical bank. Exposed cortical surface was thickly covered with tyrode agar. Systematic exploration of each area was carried out to determine the changes in various gyri. The left sciatic nerve was exposed at the popliteal level. After completion of surgery, the animals were rested without recording until the corneal reflex reappeared with reduction of the effects of the initially administered pentobarbital. Wound margins and pressure points were treated minutely by infiltration of xylocaine hydrochloride, which was readministered periodically during the experiment. Attention was payed throughout the experiment on the pupils, as an index of painless state, which were smaller than medium size in diameter except when the animals were subjected to the external stimuli. All of the experimental procedures was carefully arranged to confine the external stimuli to the minimum necessity. The situation with (1) repetitive electrical stimulation of the sciatic nerve with an intensity 10 ~o above the thresholds activating A6 and C fibers (usually over 125 mA; pulse duration, 0.5 msec) at 10-100 Hz; or (2) perfusion of bradykinin (25 #g/ml in 0.9% sodium chloride solution) into the right lower extremity (25 /zg), was studied. Each animal was subjected twice to sciatic stimulation with different cycles and twice to bradykinin perfusion with sufficient intervals. These procedures were completed within 1.5 h from the time of the reappearance of the corneal reflex and immediately followed by an administration of an overdose of pentobarbital. In 3 animals, minimum necessary period of repetitive sciatic nerve stimulation to induce noticeable changes in L-CBF was assessed and it was shown that a period of 30 sec was required. Based on this result, only the effects of stimulation with a period of 30 sec were investigated in remaining cats. Each animal was made to inhale 5 ~ hydrogen gas for 30 sec starting 1 min after the onset of electrical stimulation or bradykinin perfusion. In 8 animals, the effects of electrolytic destruction of the ventromedial, ventrolateral or dorsal
TABLE I Changes of I-CBF in the gyrus proreus induced by repetitive stimulation of the left sciatic nerve with noxious intensity
Values were obtained from 10 different cats. Stim. ( Hz)
Control 10 20 40 60 100 * P <: 0.05.
l-CBF in gyrus proreus ( ml/ l O0 g /min ) Right
Left
44.0 :~ 6.4 64.6 ± 6.1" 60.7 ± 6.4* 51.3 ± 4.9 50.9 i 6.2 50.4 ± 5.3
45.1 ± 5.9 65.7 ± 6.8* 61.0 ± 6.4* 50.9 :j__5.1 49.9 ± 5.6 49.8 ± 5.2
181 TABLE II
Changes in the averaged CBF of various cortical areas induced by bradykinin perfusion into the right lower extremity CBF (ml/lO0 g/min)
Lt-frontal area* Rt-frontal area* Lt-parietal area Lt-occipital area
Control
Bradykinin perfusion
42.5 44.6 51.7 42.2
83.2 88.1 60.7 48.0
:E 7.1 :E 5.4 :E 6.6 :E 4.2
4- 19.2"* -4- 14.9"* :E 11.3"** ± 8.5
* Including the posterior sigmoid gyrus. ** P < 0.005. *** P < 0.05.
H2 CL CURVI
I0 mV
CBF
IO W TEMP.
0.5
°C
SBP I00 5O BRADYKININ
I
I
I min Fig. 1. Example of the time course of CBF in the frontal area, systemic arterial pressure, and heart rate. CBF was measured by the thermoelectric technique.
182 TABLE III Effects o f pretreatment by an intraventricular injection o f 6-OHDA (400-500 #g) on the CBF increase in the frontal area induced by bradykinin perfusion into the lower extremity CBF in left frontal area (ml/lO0 g/min)
Untreated 6-OHDApretreated
Control
Bradykinin perfusion
42.5 i 7.1 52.3 _-k_7.8
83.2 ± 19.2" 66.8 ± 15.1"*
* P < 0.005. ** P < 0.05. thalamus on changes in L-CBF induced by noxious stimuli were studied. The surgical and recording procedures were as described in detail elsewherO
183
175
,'9.5
Fig. 2. Diagrammatic view of the coronal sections indicating ventromedial thalamic lesion which was made bilaterally and shown to avert induction of a CBF increase in the frontal area by noxious stimuli. CL, central lateral nucleus; CM, central medial nucleus; GL, lateral geniculate body; GM, medial geniculate body; HL, lateral habenular nucleus; LD, lateral dorsal nucleus; LP, lateral posterior nucleus; MD, medial dorsal nucleus; MM, medial mammillary nucleus; NCM, center median nucleus; PC, paracentral nucleus; PP, pes pedunculi.
Bilateral ventromedial thalamic lesions, including the greater part of the center median nucleus, the parafascicular nucleus, and habenulointerpeduncular tract, the caudal lower part of the dorsal medial nucleus, part of the nucleus of the posterior commissure, the nucleus limitans, and the central gray (Fig. 2), seriously suppressed the CBF increase in the frontal area. The CBF values increased only from 40.8 -I- 6.3 to 48.6 ± 8.6 ml/100 g/min, i.e. a 19 ~ increase from the resting value (Table IV). This difference was not statistically significant. On the other hand, bilateral ventrolateral thalamic lesions, including the greater part of the ventral posterolateral nucleus, fields of Forel, and ventral posteromedial nucleus, showed almost no effect. Bilateral dorsal thalamic lesions, which involved the greater part of the medial dorsal nucleus, medial half of the lateral medial nucleus, upper half of the center median nucleus, medial part TABLE IV
Effects of various thalamic lesions on the CBF increase in the left frontal area induced by bradykinin perfusion into the right lower extremity Thalamic lesion
Dorsal thalamus Ventrolateral thalamus Ventromedial thalamus * P < 0.05. ** NS.
CBF in left frontal area (ml/lO0 g/min) Control
Bradykinin perfusion
42.0 i 5.3 54.3 ± 8.6 40.8 ± 6.3
74.7 4- 9.2* 103.9 -k 16.4" 48.6 q- 8.6**
184 of the central lateral nucleus and the habenular nucleus, also revealed no significant effect. The CBF in the frontal area increased from 42.0 ± 5.3 to 74.7 ± 9.2 ml/100 g/min, i.e. a 79 ~ increase from the resting value, in spite of receiving the bilateral dorsal thalamic lesions. The first point which should be considered in relation to these results is whether the CBF increases are not produced by a raised systemic arterial pressure or heart rate. Raised arterial pressure and heart rate are thought to be manifestations of subjective pain experience. The different time courses of the CBF increase and raised arterial pressure or heart rate may provide an answer to this question (Fig. 1). The difference in time course may be well interpreted as the time lag to induce a CBF increase by raised neuronal activity. It has been reported that a time lag of over 1 min exists between acceleration of cerebral metabolism resulting from raised neuronal activity and increase of the CBF 11. This observation could therefore represent indirect evidence favoring the CBF increase resulting from acceleration of the cerebral metabolism in the frontal area related to pain experience. Naturally, a raised arterial pressure or heart rate does not reflect on a CBF increase restricted to the frontal area. While bilateral dorsal or ventrolateral thalamic lesions did not exert significant effect on the CBF increase in the frontal, bilateral ventromedial thalamic lesions averted it almost completely (Table IV). This suggests that CBF increases in the frontal area are intimately related to the activity of the subcortical pain pathwayT,lz, ~3. Although the non-specific reticular activating system activated by noxious stimuli might play a partial role, especially in diffuse CBF increases spread over the entire cerebral cortex 8, it can be concluded that increased activities of an appreciable population of neurons in the frontal cortex activated through the subcortical pain pathway might be related to a CBF increase restricted to the frontal area. CBF increase in the frontal area was significantly reduced by chemical denervation of the catecholaminergic system (Table III). Although further studies are required to determine the precise role of the catecholaminergic system, there appears to be some justification for considering that this finding may be related to at least two types of observations: (1) destruction of noradrenalin fibers has been shown to increase the pain threshold 3,~°, therefore, CBF increase in the frontal area related to pain may be reduced; and (2) destruction of noradrenalin fibers has been reported to exert a serious effect on the normal relationships between neuronal activity and CBF2,4,9,'4; thus, CBF increase may be impaired despite pain mechanism being preserved. These two possibilities appear to be interrelated when the idea that the catecholaminergic system may be involved in the cerebral oxidative metabolism in situ 6 is taken into consideration. Based on the present results and other available evidencO 4A5, it is concluded that the CBF increase in the frontal area induced by noxious stimuli provides possible evidence favoring involvement of the frontal cortex in pain-related cerebral events in the cat. This work was supported by a Japan Education Ministry Grant.
185 1 Aukland, K., Bower, B. F. and Berliner, R. W., Measurement of local blood flow with hydrogen gas, Circulat. Res., 14 (1964) 164--187. 2 Bates, D., Weinshilboum, R. M., Campbell, R. J. and Sundt, T. M. Jr., The effect of lesions in the locus coeruleus on the physiological responses of the cerebral blood vessels in cats, Brain Research, 136 (1977) 431-443. 3 Bodnar, R. J., Ackerman, R. F., Kelly, D. D. and Glusman, M., Elevations in nociceptive thresholds following locus coeruleus lesions, Brain Res. Bull., 3 (1978) 125-130. 4 Edvinsson, L., Hardebo, J. E. and MacKenzie, E. T., Effects of intraventricular 6-hydroxydopamine on cerebrovascular CO2 reactivity in anesthetized rats, Acta physioL scand., 101 (1977) 122-125. 5 Hand, P. J., Greenberg, J., Goochee, G., Sylvesno, A., Weller, L. and Reivich, M., A normal and developmentally altered cortical column. A laminar analysis of local glucose utilization with natural stimulation of a single receptor organ, Acta neurol, scand., Suppl. 72 (1979) 46--47. 6 Harik, S. I., LaManna, J. C., Light, A. I. and Rosenthal, M., Cerebral norepinephrine: influence on cortical oxidative metabolism in situ, Science, 206 (1979) 69-70. 7 Hassler, R., Dichotomy of facial pain conduction in the diencephalon. In R. Hassler and A. R. Walker (Eds.), Trigeminal Neuralgia, George Thieme, Stuttgard, 1970, pp. 121-138. 8 Ingvar, D. H., Extraneural influences upon the electrical activity of isolated cortex following stimulation of the reticular activating system, Acta physioL scand., 33 (1955) 169-193. 9 Mendelow, A. P., McCalden, T. A., Hattingh, J., Kramer, B., Rosendorff, C. and Eidelman, B. H., The effect of chemical sympathectomy on cerebrovascular reactivity and cerebral metabolism. In C. Owman and L. Edvinsson (Eds.), Neurogenic Control of Brain Circulation, Pergamon Press, Oxford, 1977, pp. 429-442. 10 Sasa, M., Munekiyo, K., Osuari, Y. and Takaoni, S., Attenuation of morphine analgesia in rats with lesions of the locus coeruleus and dorsal raphe nucleus, Europ. J. PharmacoL, 42 (1977) 53-62. 11 Sokoloff, L., Local cerebral energy metabolism, its relationships to local functional activity and blood flow. In Cerebral Vascular Smooth Muscle and Its Control, Ciba Foundation Symposium 56, Elsevier, Amsterdam, 1978, pp. 171-197. 12 Tsubokawa, T., The correlation of pain relief, neurological signs, EEG and anatomical lesion sites in pain patients treated by stereotaxic thalamotomy, Folia physchiat, neurol, jap., 21 (1967) 41-50. 13 Tsubokawa, T. and Moriyasu, N., Follow-up results of centre median thalamotomy for relief of intractable pain, Confin. neuroL (Basel), 37 (1975) 280-284. 14 Tsubokawa, T., Katayama, Y., Kondo, T., Veno, Y., Hayashi, N. and Moriyasu, N., Changes in local cerebral blood flow and neuronal activity during sensory stimulation in normal and sympathectomized cats, Brain Research, 190 (1980) 51-65. 15 Ueno, Y., Changes in local cerebral blood flow by afferent stimulation: The role of intracerebral monoaminergic system, Nihon Univ. J. Med., 39 (1980) 387-403.