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Responses of neurons in the ventromedial midbrain to noxious mechanical stimuli
Neuroscience Letters, 133 (1991)215-218
215
© 1991 ElsevierScientificPublishers Ireland Ltd. All rights reserved0304-3940/91/$03.50 NSL 08230
Responses of neurons in the ventromedial midbrain to noxious mechanical stimuli I a n D. Hentall, Julie L. K i m a n d L a k s h m i G o l l a p u d i Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107-1897 (U.S.A.)
(Received31 May 1991;Revisedversion received28 August 1991;Accepted30 August 1991) Key words: Pain;Interpeduncular;A10; Ventral tegmental area
Neurons of the ventromedialmidbrain in pentobarbital-anesthetizedrats were examined by extracellularrecording for responses to mechanical stimulation of the skin. Responses were absent from neurons clearly located in the interpeduncularnucleus (IPN) (n = 20), and from 92% of linear raphe (LR) neurons (n = 26). However,37%of neurons in the ventral tegmentalarea of Tsai (VTA)(n = 38) and 63~ of neurons in the small interfascicular nucleus (IF) (n=9) were inhibited, often recoveringwith a delay of 1-2 min. A few ceils (n=4) were weakly excited in these 4 nuclei; none responded to innocuous mechanical stimulation of the skin. It is concluded that noxious cutaneous stimuli will not modify (by feedback) any influenceof the IPN on pain perception,but could dampen behavior-reinforcingeffectsof the VTA and IF.
The medial ventral midbrain contains two principal cell groupings: the midline interpeduncular nucleus (IPN) and the bilateral A10 region. The IPN is of uncertain primary function [18, 23], but an influence on central pain processing is indicated by some evidence. For example, electrically stimulating the habenulae [3, 24], whose medial divisions form a major source of descending input to the IPN, reduces pain sensation; so also does lesioning the fasciculus retroflexus (FR) [17], which consists mainly of habenulo-interpeduncular fibers. Neurons of the nucleus raphe magnus, a significant region for pain modulation [1], are inhibited or excited (depending on their sensory response class) by chemical or electrical stimulation of the IPN [2, 10]. Besides the IPN, the ventromedial midbrain contains the ventral tegmental area of Tsai (VTA), the interfascicular nucleus (IF) and the linear raphe nucleus (LR) [19, 21]. Some evidence suggests that forebrain projections of the A10 dopaminergic region control behavioral reinforcement and may play a role in addiction to cocaine and other abused drugs [6, 13]. The potential importance of nociceptive modulation of reinforcement, in addition to the above data connecting the IPN with pain processing, prompted the present microelectrode mapping study of
Correspondence: I.D. Hentall, Department of Biomedical Sciences, University of Illinois Collegeof Medicine at Rockford, Rockford, IL 61107-1897,U.S.A. Fax: (1)(815) 395-5887.
responses to noxious and innocuous mechanical stimulation. Ten rats (female, Sprague-Dawley breed, weight 240308 g) were anesthetized with sodium pentobarbital (60 mg/kg, i.m.). The trachea was intubated, and one of the jugular veins was cannulated to allow maintenance of anesthesia by a continuous infusion of sodium methohexital (5-14 mg/kg/h) via a syringe pump. Body temperature was kept at 37°C by a heating pad controlled by feedback from a rectal thermistor. Extracellular recordings were made with glass micropipettes (impedance of 2-4 Mr2) filled with a solution of 2 M sodium acetate and saturated Fast green dye. Target co-ordinates extended 1.9-3.4 mm rostrocaudally, 0.53.0 mm dorsoventrally, and 1 mm bilaterally across the midline [20]. To search for nociceptive responses, constant pressure (approximately 0.06-0.12 newtons (N) over an area o f 20 mm z) was applied with a hemostat to the rat's tail, forepaw, hindpaw, and cheek. This stimulus was given at least every 50/lm in the vertical microelectrode trajectory. Brushing of the skin was performed to inspect for non-noxious mechanoceptive responses. In five rats, a pair of modified tungsten microelectrodes with exposed tips of 100/~m provided monopolar electrical search stimuli (0.2 ms rectangular pulses, 6-30 V, 1 Hz) bilaterally in the fasciculus retroflexus or medial habenula (MHb). Electrode tip positions were marked by injecting Fast green dye; (3-5/IA pulses, 4.5 ms width, 200 Hz frequen-
216
C R°
!
_ ~
÷o
+ = excitation, - = inhibition, o = no effect Fig. I. The locations of units whose response to noxious pinching of the skin was tested, and of MHb/FR stimulation sites. Recording sites from different rostrocaudal levelswere mapped onto the nearer of the two composite pictures: A, 3.3 mm anterior to the interaural line; B 2.5 mm anterior. The cell on the boundary of the IPN and VTA in B was classifiedas being in the IPN. The filled rectangles in C depict the sites of successful MHb/FR stimulation. IPN, interpeduncular nucleus; VTA, ventral tegmental area; IF, interfascicular nucleus; LR, linear raphe nucleus: Hb, habenula; fr, fasciculus retroflexus; 3V, third ventricle.
cy, for 15-20 min). Lesions in the F R or M H b were made by passing bipolar pulses across the pair of electrodes (100 V amplitude, 4.5 ms pulse width, 200 Hz frequency, for 10 min). Dye marks were found post-mortem in 50/tm coronal sections stained with Cresyl violet, and the positions of recorded cells were noted on standard diagrams (Fig. 1A,B) derived from published anatomical descriptions [7, 21]. The Fisher exact test was used for testing significance. A total of 93 neurons were tested with the noxious stimuli (Table I); 63 of these were tested for synaptic responses to stimulation of the M H b or FR, and 7 cells were tested with the M H b / F R stimulation but not the cutaneous stimulation. Inhibitory responses were found only in the VTA and IF. Four cells in the entire mapped region studied were judged to have a weak excitatory response (all < 20% of resting activity). No cells were observed to respond to innocuous mechanical stimulation of the skin. The ratio of inhibited to unaffected cells showed highly significant differences (P < 0.001) between all testable pairs of nuclei except the VTA and IF (P = 0.26). The I P N and LR could not be compared statistically since neither had cells with inhibitory responses. Thus two zones emerge from mapping the responses to mechanical stimulation of the skin in the cytoarchitecturally and cytochemically defined nuclei of the ventromedial midbrain. In the I P N and LR there is a near absence of responses, but in the region of the VTA and IF slightly fewer than 50% of neurons are inhibited by noxious stimulation and a small proportion are excited. The spontaneous activity of all neurons in the VTA and IF fell into the previously described type I class that is thought to be dopaminergic [15, 26]: spikes lasted > 2 ms, and their firing was regular ( < 8 Hz) or cyclically modulated (3-8 s). In some cells, the time-course of the skin stimulus was mirrored fairly closely; in others, the
inhibition outlasted stimulus application by 1-2 min. These varieties of response could be seen between trials on a given cell (Fig. 2). U p o n electrical stimulation of the M H b or FR, synaptic excitation was seen in 38% of I P N neurons ( n = 16), 78% of IF neurons (n = 9), 9% of LR neurons (n = 22), and 21% 0f VTA neurons (n=24). Excitation was not seen when the stimulating electrode was moved 1 m m above or below the target. Latencies varied from 5-20 ms. Statistically, significant differences were found between the IF and all other nuclei, and between the I P N and LR ( P < 0.05). No cells excited by M H b / F R stimulation were found in the medial third of the I P N ( P < 0.005). The VTA cells driven by M H b / F R stimulation were all located in the ventral half, below the dorsal limit of the IF. This corresponds to the division of the VTA into the nucleus paranigralis (ventral) and the nucleus parabrachialis pigmentosus (dorsal) [21]. Excitation of neurons in the I P N and IF by M H b / F R stimulation is consistent with anatomical data on pathways, since a projection from the M H b to the IF has been described [22], in addition to the well known projection of the M H b to the IPN. None has been described for the LR or VTA. The 38% of sampled neurons excited here by M H b / F R stimulation is comparable to the 43% reported in the cat [14]. The present sampling could not resolve the 8 cytoarchitecturally and cytochemically distinct subnuclei [7, 18], but it did show cells driven by M H b / F R stimulation to be confined to lateral parts of the IPN, which is where substance P staining is localized and choline acetyltransferase staining is absent [4]. Our findings in the A10 region agree with a recent study in rats anesthetized with a mixture of urethane and chloral hydrate [16] which found that 68% of mesocortically projecting dopaminergic A 10 cells are inhibited and 13% are excited by noxious mechanical stimulation; few mesolimbically projecting neurons were responsive.
217 TABLE I
Supported by PHS Grant NS 26116 and the Earl Bane Charitable Trust.
THE EFFECT OF NOXIOUS STIMULATION OF THE SKIN ON THE ACTIVITY OF NEURONS IN THE VENTROMEDIAL MIDBRAIN The first numbers are the total neurons responding, and the numbers in parentheses are the row percentages. Inhibition
No effect
Excitation
5 (62.5%) 0 (0%) 0 (0%) 14 (37%)
3 (37.5%) 20 (95%) 24 (92%) 22 (58%)
0 (0%) 1 (5%) 2 (8%) 2 (5%)
IF IPN LR VTA
1 Besson, J.-M. and Chaouch, A., Peripheral and spinal mechanisms of nociception, Physiol. Rev., 67 (1987) 67-186. 2 Budhrani, V. and Hentall, I.D., Acetylcholine, glutamate, GABA, and electrical stimulation in the interpeduncular nucleus systematically influence the activity of on and off cells in the nucleus raphe magnus, Soc. Neurosci. Abstr., 15 (1989) 182. 3 Cohen, R.S. and Melzack, R., Habenular stimulation produces analgesia in the formalin test, Neurosci. Lett., 70 (1986) 165-169. 4 Contestabile, A., Villani, L., Fasolo, A., Franzoni, M.F., Gribaudo, L., Oktedalen, O. and Fonnum, F., Topography of cholinergic and substance P pathways in the habenulo-interpeduncular system of the rat. An immunocytochemical and microchemical approach, Neuroscience, 21 (1987) 253-270. 5 Fields, H.L, Vanegas, H., Hentall, I.D. and Zorman, G., Evidence that disinhibition of brain stem neurones contributes to morphine analgesia, Nature, 306 (1983) 684-686. 6 Goeders, N.E. and Smith, J.E., Cortical dopaminergic involvement in cocaine reinforcement, Science, 221 (1983) 733-735. 7 Groenewegen, H.J., Ahlenius, S., Haber, S.N., Kowall, N.W. and Nauta, W.J.H., Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus of the rat, J. Comp. Neurol., 249 (1986) 65-102. 8 Haws, C.M., Williamson, A.M. and Fields, H.L., Putative nociceptive modulatory neurons in the dorsolateral pontomesencephalic reticular formation, Brain Res., 483 (1989) 272-282. 9 Heinricher, M.M., Cheng, Z.F. and Fields, H.L., Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray, J. Neurosci., 7 (1987) 271-278. 10 Hentall, I.D. and Budhrani, V.M., The interpeduncular nucleus excites the on-cells and inhibits the off-cells in the nucleus rapbe magnus, Brain Res., 522 (1990) 322 324. 11 Kai, Y., Oomura, Y. and Shimuzu, N., Responses of rat lateral hypothalamic neurons to periaqueductal gray stimulation and nociceptive stimuli, Brain Res., 461 (1988) 107-117. 12 Kiaytkin, E.A., Functional properties of presumed dopamine-con-
However, in awake rats [12], only those VTA neurons postulated to be GABAergic or cholinergic were depressed by aversive stimuli, while presumed dopaminergic cells were mostly excited. Similarly, in ketamineanesthetized rats [15], dopaminergic A10 neurons projecting to various parts of the forebrain were found to be unaffected (69%) or sometimes excited (18%), but infrequently inhibited (13%). In conclusion, the lack of neuronal responses to noxious mechanical stimuli in the IPN contrasts with the high proportion of nociceptive neurons in such wellknown pain-controlling brainstem areas as the nucleus raphe magnus [5, 25], the periaqueductal gray matter [9], the lateral hypothalamus [11], the parabrachial region [8], and the nucleus cuneiformis [8]. Prolonged inhibition of dopaminergic neurons in the VTA and IF by brief, noxious mechanical stimuli could reflect modulation of the behavioral reinforcement that has been proposed to be a function of their forebrain projections [6, 13].
B T
T
v
v
o c © -7
o c 7 o-
& r-"~_
c
o-4--
4--
o
1 oo
200 time
300 (s)
400
o
1 oo
200 time
300
400
(s)
Fig. 2. Examples of the inhibition in the interfascicular nucleus (A) and the ventral tegmental area of Tsai (B). The duration of the pinch stimulus is indicated by the unfilled columns. Activity was sampled in 2 s bins. In A, the first stimulus application produced a long-lasting drop in activity.; the next two stimulus applications led to inhibition that did not greatly outlast the stimulus. In B, The first stimulus application caused inhibition that recovered in about 100 s, and the second stimulus application also produced a long-lasting inhibition. Although many neurons had cycling rates of activity (e.g. A), the existence of inhibition could be inferred by the consistency of the coincidence with stimulus application.
218
13 14 15
16
17
18 19
taining and other ventral tegmental area neurons in conscious rats, Int. J. Neurosci., 42 (1988) 21-43. Koob, G.F. and Bloom, F.E., Cellular and molecular mechanisms of drug dependence, Science, 242 (I 988) 715-723. Lake, N., Studies of the habenulo-interpeduncular pathway in cats. Exp. Neurol., 41 (1973) 113-132. Maeda, H. and Mogenson, G.J., Effects of peripheral stimulation on the activity of neurons in the ventral tegmental area, substantia nigra and midbrain reticular formation of rats, Brain Res. Bull., 8 (1982) 7-14. Mantz, J., Thierry, A.M. and Glowinski, J., Effect of noxious tail pinch on the discharge rate of mesocortical and mesolimbic dopamine neurons: selective activation of the mesocortical system, Brain Res., 476 (1989) 377-381. Meszaros, J., Gajewska, S. and Tarchalska-Krynska, B., Habenulo-interpeduncular lesions: the effects on pain sensitivity, morphine analgesia and open-field behavior in rats, Pol. J. Pharm. Pharmacol., 37 (1985) 469-477. Morley, B.J., The interpeduncular nucleus, Int. Rev. Neurobiol., 8 (1986) 157 182. Palkowits, M. and Jacobowitz, D.M., Topographic atlas of catecholamine and acetylcholinesterase-containing neurons in the rat
20 21
22
23
24
25
26
brain. II. Hindbrain (mesencephalon, rhombencephalon), J. Comp. Neurol., 157 (1974) 29-42. Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, 2nd edn., Academic Press, Orlando, 1986. Phillipson, O.T., The cytoarchitecture of the interfascicular nucleus and the ventral tegmental area of Tsai in the rat, J. Comp. Neurol., 187 (1979) 85-98. Phillipson, O.T., Afferent projections to the ventral tegmental area of Tsai: a horseradish peroxidase study in the rat, J. Comp. Neurol., 187(1979) 117 144. Sutherland, R.J., The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex, Neurosci. Biobehav. Rev., 6 (1982) 1 13. Terenzi, M.G. and Prado, W.A. Antinociception elicited by electrical or chemical stimulation of the rat habenular complex and its sensitivity to systemic antagonists, Brain Res., 535 (1990) 18-24. Vanegas, H., Barbaro, N. and Fields, H.L., Midbrain stimulation inhibits tail-flick only at currents sufficient to excite rostral medullary neurons, Brain Res., 321 (1984) 127-133. Wang, R.Y., Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization, Brain Res. Rev., 3 (1981) 123-140.
215
© 1991 ElsevierScientificPublishers Ireland Ltd. All rights reserved0304-3940/91/$03.50 NSL 08230
Responses of neurons in the ventromedial midbrain to noxious mechanical stimuli I a n D. Hentall, Julie L. K i m a n d L a k s h m i G o l l a p u d i Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107-1897 (U.S.A.)
(Received31 May 1991;Revisedversion received28 August 1991;Accepted30 August 1991) Key words: Pain;Interpeduncular;A10; Ventral tegmental area
Neurons of the ventromedialmidbrain in pentobarbital-anesthetizedrats were examined by extracellularrecording for responses to mechanical stimulation of the skin. Responses were absent from neurons clearly located in the interpeduncularnucleus (IPN) (n = 20), and from 92% of linear raphe (LR) neurons (n = 26). However,37%of neurons in the ventral tegmentalarea of Tsai (VTA)(n = 38) and 63~ of neurons in the small interfascicular nucleus (IF) (n=9) were inhibited, often recoveringwith a delay of 1-2 min. A few ceils (n=4) were weakly excited in these 4 nuclei; none responded to innocuous mechanical stimulation of the skin. It is concluded that noxious cutaneous stimuli will not modify (by feedback) any influenceof the IPN on pain perception,but could dampen behavior-reinforcingeffectsof the VTA and IF.
The medial ventral midbrain contains two principal cell groupings: the midline interpeduncular nucleus (IPN) and the bilateral A10 region. The IPN is of uncertain primary function [18, 23], but an influence on central pain processing is indicated by some evidence. For example, electrically stimulating the habenulae [3, 24], whose medial divisions form a major source of descending input to the IPN, reduces pain sensation; so also does lesioning the fasciculus retroflexus (FR) [17], which consists mainly of habenulo-interpeduncular fibers. Neurons of the nucleus raphe magnus, a significant region for pain modulation [1], are inhibited or excited (depending on their sensory response class) by chemical or electrical stimulation of the IPN [2, 10]. Besides the IPN, the ventromedial midbrain contains the ventral tegmental area of Tsai (VTA), the interfascicular nucleus (IF) and the linear raphe nucleus (LR) [19, 21]. Some evidence suggests that forebrain projections of the A10 dopaminergic region control behavioral reinforcement and may play a role in addiction to cocaine and other abused drugs [6, 13]. The potential importance of nociceptive modulation of reinforcement, in addition to the above data connecting the IPN with pain processing, prompted the present microelectrode mapping study of
Correspondence: I.D. Hentall, Department of Biomedical Sciences, University of Illinois Collegeof Medicine at Rockford, Rockford, IL 61107-1897,U.S.A. Fax: (1)(815) 395-5887.
responses to noxious and innocuous mechanical stimulation. Ten rats (female, Sprague-Dawley breed, weight 240308 g) were anesthetized with sodium pentobarbital (60 mg/kg, i.m.). The trachea was intubated, and one of the jugular veins was cannulated to allow maintenance of anesthesia by a continuous infusion of sodium methohexital (5-14 mg/kg/h) via a syringe pump. Body temperature was kept at 37°C by a heating pad controlled by feedback from a rectal thermistor. Extracellular recordings were made with glass micropipettes (impedance of 2-4 Mr2) filled with a solution of 2 M sodium acetate and saturated Fast green dye. Target co-ordinates extended 1.9-3.4 mm rostrocaudally, 0.53.0 mm dorsoventrally, and 1 mm bilaterally across the midline [20]. To search for nociceptive responses, constant pressure (approximately 0.06-0.12 newtons (N) over an area o f 20 mm z) was applied with a hemostat to the rat's tail, forepaw, hindpaw, and cheek. This stimulus was given at least every 50/lm in the vertical microelectrode trajectory. Brushing of the skin was performed to inspect for non-noxious mechanoceptive responses. In five rats, a pair of modified tungsten microelectrodes with exposed tips of 100/~m provided monopolar electrical search stimuli (0.2 ms rectangular pulses, 6-30 V, 1 Hz) bilaterally in the fasciculus retroflexus or medial habenula (MHb). Electrode tip positions were marked by injecting Fast green dye; (3-5/IA pulses, 4.5 ms width, 200 Hz frequen-
216
C R°
!
_ ~
÷o
+ = excitation, - = inhibition, o = no effect Fig. I. The locations of units whose response to noxious pinching of the skin was tested, and of MHb/FR stimulation sites. Recording sites from different rostrocaudal levelswere mapped onto the nearer of the two composite pictures: A, 3.3 mm anterior to the interaural line; B 2.5 mm anterior. The cell on the boundary of the IPN and VTA in B was classifiedas being in the IPN. The filled rectangles in C depict the sites of successful MHb/FR stimulation. IPN, interpeduncular nucleus; VTA, ventral tegmental area; IF, interfascicular nucleus; LR, linear raphe nucleus: Hb, habenula; fr, fasciculus retroflexus; 3V, third ventricle.
cy, for 15-20 min). Lesions in the F R or M H b were made by passing bipolar pulses across the pair of electrodes (100 V amplitude, 4.5 ms pulse width, 200 Hz frequency, for 10 min). Dye marks were found post-mortem in 50/tm coronal sections stained with Cresyl violet, and the positions of recorded cells were noted on standard diagrams (Fig. 1A,B) derived from published anatomical descriptions [7, 21]. The Fisher exact test was used for testing significance. A total of 93 neurons were tested with the noxious stimuli (Table I); 63 of these were tested for synaptic responses to stimulation of the M H b or FR, and 7 cells were tested with the M H b / F R stimulation but not the cutaneous stimulation. Inhibitory responses were found only in the VTA and IF. Four cells in the entire mapped region studied were judged to have a weak excitatory response (all < 20% of resting activity). No cells were observed to respond to innocuous mechanical stimulation of the skin. The ratio of inhibited to unaffected cells showed highly significant differences (P < 0.001) between all testable pairs of nuclei except the VTA and IF (P = 0.26). The I P N and LR could not be compared statistically since neither had cells with inhibitory responses. Thus two zones emerge from mapping the responses to mechanical stimulation of the skin in the cytoarchitecturally and cytochemically defined nuclei of the ventromedial midbrain. In the I P N and LR there is a near absence of responses, but in the region of the VTA and IF slightly fewer than 50% of neurons are inhibited by noxious stimulation and a small proportion are excited. The spontaneous activity of all neurons in the VTA and IF fell into the previously described type I class that is thought to be dopaminergic [15, 26]: spikes lasted > 2 ms, and their firing was regular ( < 8 Hz) or cyclically modulated (3-8 s). In some cells, the time-course of the skin stimulus was mirrored fairly closely; in others, the
inhibition outlasted stimulus application by 1-2 min. These varieties of response could be seen between trials on a given cell (Fig. 2). U p o n electrical stimulation of the M H b or FR, synaptic excitation was seen in 38% of I P N neurons ( n = 16), 78% of IF neurons (n = 9), 9% of LR neurons (n = 22), and 21% 0f VTA neurons (n=24). Excitation was not seen when the stimulating electrode was moved 1 m m above or below the target. Latencies varied from 5-20 ms. Statistically, significant differences were found between the IF and all other nuclei, and between the I P N and LR ( P < 0.05). No cells excited by M H b / F R stimulation were found in the medial third of the I P N ( P < 0.005). The VTA cells driven by M H b / F R stimulation were all located in the ventral half, below the dorsal limit of the IF. This corresponds to the division of the VTA into the nucleus paranigralis (ventral) and the nucleus parabrachialis pigmentosus (dorsal) [21]. Excitation of neurons in the I P N and IF by M H b / F R stimulation is consistent with anatomical data on pathways, since a projection from the M H b to the IF has been described [22], in addition to the well known projection of the M H b to the IPN. None has been described for the LR or VTA. The 38% of sampled neurons excited here by M H b / F R stimulation is comparable to the 43% reported in the cat [14]. The present sampling could not resolve the 8 cytoarchitecturally and cytochemically distinct subnuclei [7, 18], but it did show cells driven by M H b / F R stimulation to be confined to lateral parts of the IPN, which is where substance P staining is localized and choline acetyltransferase staining is absent [4]. Our findings in the A10 region agree with a recent study in rats anesthetized with a mixture of urethane and chloral hydrate [16] which found that 68% of mesocortically projecting dopaminergic A 10 cells are inhibited and 13% are excited by noxious mechanical stimulation; few mesolimbically projecting neurons were responsive.
217 TABLE I
Supported by PHS Grant NS 26116 and the Earl Bane Charitable Trust.
THE EFFECT OF NOXIOUS STIMULATION OF THE SKIN ON THE ACTIVITY OF NEURONS IN THE VENTROMEDIAL MIDBRAIN The first numbers are the total neurons responding, and the numbers in parentheses are the row percentages. Inhibition
No effect
Excitation
5 (62.5%) 0 (0%) 0 (0%) 14 (37%)
3 (37.5%) 20 (95%) 24 (92%) 22 (58%)
0 (0%) 1 (5%) 2 (8%) 2 (5%)
IF IPN LR VTA
1 Besson, J.-M. and Chaouch, A., Peripheral and spinal mechanisms of nociception, Physiol. Rev., 67 (1987) 67-186. 2 Budhrani, V. and Hentall, I.D., Acetylcholine, glutamate, GABA, and electrical stimulation in the interpeduncular nucleus systematically influence the activity of on and off cells in the nucleus raphe magnus, Soc. Neurosci. Abstr., 15 (1989) 182. 3 Cohen, R.S. and Melzack, R., Habenular stimulation produces analgesia in the formalin test, Neurosci. Lett., 70 (1986) 165-169. 4 Contestabile, A., Villani, L., Fasolo, A., Franzoni, M.F., Gribaudo, L., Oktedalen, O. and Fonnum, F., Topography of cholinergic and substance P pathways in the habenulo-interpeduncular system of the rat. An immunocytochemical and microchemical approach, Neuroscience, 21 (1987) 253-270. 5 Fields, H.L, Vanegas, H., Hentall, I.D. and Zorman, G., Evidence that disinhibition of brain stem neurones contributes to morphine analgesia, Nature, 306 (1983) 684-686. 6 Goeders, N.E. and Smith, J.E., Cortical dopaminergic involvement in cocaine reinforcement, Science, 221 (1983) 733-735. 7 Groenewegen, H.J., Ahlenius, S., Haber, S.N., Kowall, N.W. and Nauta, W.J.H., Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus of the rat, J. Comp. Neurol., 249 (1986) 65-102. 8 Haws, C.M., Williamson, A.M. and Fields, H.L., Putative nociceptive modulatory neurons in the dorsolateral pontomesencephalic reticular formation, Brain Res., 483 (1989) 272-282. 9 Heinricher, M.M., Cheng, Z.F. and Fields, H.L., Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray, J. Neurosci., 7 (1987) 271-278. 10 Hentall, I.D. and Budhrani, V.M., The interpeduncular nucleus excites the on-cells and inhibits the off-cells in the nucleus rapbe magnus, Brain Res., 522 (1990) 322 324. 11 Kai, Y., Oomura, Y. and Shimuzu, N., Responses of rat lateral hypothalamic neurons to periaqueductal gray stimulation and nociceptive stimuli, Brain Res., 461 (1988) 107-117. 12 Kiaytkin, E.A., Functional properties of presumed dopamine-con-
However, in awake rats [12], only those VTA neurons postulated to be GABAergic or cholinergic were depressed by aversive stimuli, while presumed dopaminergic cells were mostly excited. Similarly, in ketamineanesthetized rats [15], dopaminergic A10 neurons projecting to various parts of the forebrain were found to be unaffected (69%) or sometimes excited (18%), but infrequently inhibited (13%). In conclusion, the lack of neuronal responses to noxious mechanical stimuli in the IPN contrasts with the high proportion of nociceptive neurons in such wellknown pain-controlling brainstem areas as the nucleus raphe magnus [5, 25], the periaqueductal gray matter [9], the lateral hypothalamus [11], the parabrachial region [8], and the nucleus cuneiformis [8]. Prolonged inhibition of dopaminergic neurons in the VTA and IF by brief, noxious mechanical stimuli could reflect modulation of the behavioral reinforcement that has been proposed to be a function of their forebrain projections [6, 13].
B T
T
v
v
o c © -7
o c 7 o-
& r-"~_
c
o-4--
4--
o
1 oo
200 time
300 (s)
400
o
1 oo
200 time
300
400
(s)
Fig. 2. Examples of the inhibition in the interfascicular nucleus (A) and the ventral tegmental area of Tsai (B). The duration of the pinch stimulus is indicated by the unfilled columns. Activity was sampled in 2 s bins. In A, the first stimulus application produced a long-lasting drop in activity.; the next two stimulus applications led to inhibition that did not greatly outlast the stimulus. In B, The first stimulus application caused inhibition that recovered in about 100 s, and the second stimulus application also produced a long-lasting inhibition. Although many neurons had cycling rates of activity (e.g. A), the existence of inhibition could be inferred by the consistency of the coincidence with stimulus application.
218
13 14 15
16
17
18 19
taining and other ventral tegmental area neurons in conscious rats, Int. J. Neurosci., 42 (1988) 21-43. Koob, G.F. and Bloom, F.E., Cellular and molecular mechanisms of drug dependence, Science, 242 (I 988) 715-723. Lake, N., Studies of the habenulo-interpeduncular pathway in cats. Exp. Neurol., 41 (1973) 113-132. Maeda, H. and Mogenson, G.J., Effects of peripheral stimulation on the activity of neurons in the ventral tegmental area, substantia nigra and midbrain reticular formation of rats, Brain Res. Bull., 8 (1982) 7-14. Mantz, J., Thierry, A.M. and Glowinski, J., Effect of noxious tail pinch on the discharge rate of mesocortical and mesolimbic dopamine neurons: selective activation of the mesocortical system, Brain Res., 476 (1989) 377-381. Meszaros, J., Gajewska, S. and Tarchalska-Krynska, B., Habenulo-interpeduncular lesions: the effects on pain sensitivity, morphine analgesia and open-field behavior in rats, Pol. J. Pharm. Pharmacol., 37 (1985) 469-477. Morley, B.J., The interpeduncular nucleus, Int. Rev. Neurobiol., 8 (1986) 157 182. Palkowits, M. and Jacobowitz, D.M., Topographic atlas of catecholamine and acetylcholinesterase-containing neurons in the rat
20 21
22
23
24
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