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Dorsal raphe and external electrical stimulation modulate noxious input to single neurons in nucleus parafascicularis thalami
Brain Research Bulk-fin, Vol. 21, pp. 671-675. 0 Pergamon Press plc, 1988. Printed in the U.S.A.
0361-9230/88 $3.00 + .OO
Dorsal Raphe and External Electrical Stimulation Modulate Noxious Input to Single Neurons in Nucleus Parafascicularis Thalami J.-T. QIAO, M. SKOLNICK
AND N. DAFNY’
University of Texas Medical School at Houston, Department of Neurobiology and Anatomy and Institute for Technology, Neurophysiology Research Center, Houston, TX 77030 Received
23 February 1988
QIAO, J.-T., M. SKOLNICK AND N. DAFNY. Dorsal raphe and external electrical stimulation modulate noxious input to single neurons in nucleus parafascicularis thalami. BRAIN RES BULL 21(4) 671-675, 1988.-Spontaneous discharges
and nociceptive responses of 47 parafascicularis thalami (PF) neurons were recorded extracellularly and comparisons were made between the effects of these discharges following focal dorsal raphe stimulation (DRS) and bilateral pinnal electrical stimulation (PES). Eighty-three percent of PF neurons (N=39) responded to noxious stimulus, about 6% of the PF responsive cells (N=27) were excited during noxious stimuli and thus categorized as “nociceptive-on” cells. The remaining cells. DRS and PES 31% (N=l2) were suppressed by the noxious stimuli, and were categorized as “nociceptive-off’ neurons as well as the noxious input to these cells, while the attenuated the spontaneous activity of the “nociceptive-on” spontaneous activity of the “nociceptive-off’ cells was suppressed only following DRS and not following PES. Moreover, PES displayed disinhibiting properties, namely, it reduced the suppression effects elicited by noxious input. In conclusion, it was demonstrated that both focal DRS and noninvasive PES were effective in modulating pain input to single neurons in the PF.
Thalamic neurons
Pain
Dorsal raphe
External electrostimulation
IN recent years, several studies have indicated that responsiveness to noxious stimuli can be modulated by focal brainstem electrical stimulation (5,12) without interference with other sensory and behavioral functions (6). Moreover, transcutaneous or transcranial stimulation in different forms (4, 7, 12) have been used for more than two decades clinically to moderate intractable pain. Recently, a form of external bilateral stimulation delivered noninvasively and at much lower current amplitude than previous modes has been reported (13,19). Thus, forms of stimulation, applied through electrodes attached to the pinnae, produce naloxone antagonizable, analgesic responses in rats. The mechanisms underlying this modulatory phenomenon are not yet understood. The objective of the present study is to compare the effects of focal electrical dorsal raphe stimulation (DRS) with noninvasive pinnal (ear) electrical stimulation (PES) at the level of the parafascicularis (PF) thalami neurons. The PF nucleus is one of several well studied subcortical sites impli-
‘Requests for reprints should be addressed
cated in pain perception, and since DRS has been well demonstrated to modulate noxious input to the PF (1, 2, 8, 17) this site was selected as the target site in the present study. It was observed that PES was as effective as focal DRS in modulating noxious input to PF at a single cell level. METHOD
Twenty-three male Sprague-Dawley rats weighing 180280 g were used as subjects. Three days prior to the experiment, gold plated, stainless steel earrings were inserted into each pinna (ear) of the animals to be later used as the eiectrodes for PES (19). The site for insertion is located by determining the highest local conductivity in the area of the vertex of the antihelix using an ampmeter with an internal signal. Electrode to electrode impedance was 8+0.4 kohms. On the experimental day, the rat was anesthetized with urethane (1.2 g/kg IP) and secured in a stereotaxic frame. Craniectomy was performed and the cortex underlying the
to N. Dafny.
671
612
QIAO, SKOLNICK u
1 A.
AND DAFNY
_T.P _..1.1.1.... DRS _.-.-._PES
TIME (set)
FIG. 1. Representative frequency histograms of PF “nociceptive-on” cells before and during tail pinch (TP) application, dorsal raphe stimulation (DRS), pinnae electrical stimulation (PES), TP concomitant with DRS, and TP concomitant with PES in A, B, C, D, E and F, respectively. PF was exposed (10,16). A hole (0.6 mm in diameter) was drilled above the DR in order to position a bipolar stimulation electrode (twisted 60 pm in diameter stainless steel teflon insulated wire) within this structure. The DR electrical stimulation was composed of 0.1 msec square pulses at 10 to 20 Hz at 50 PA. In previous experiments (2) the following procedure was established to identify the location of the stimulation electrode prior to the histological confirmation: Two electrodes were used, one implanted within the mesencephalic reticular formation (MRF) and the second within the DR-PAG area. Low current (0.1 mA; 1.O to 10 Hz) delivered to MRF elicits in PF neurons driven activity and general excitation, while 0.1 to 1.0 mA 1.0 to 10 Hz delivered to DR-PAG suppresses the spontaneous activity of the PF neurons. Currents higher than 1.0 mA delivered to DR-PAG elicit activity similar to that obtained following MRF stimulation, namely the current spread to MRF. In addition, electrode locations were con-
firmed later to be within the target sites. Thus, we used low-current (50 kA) delivery to DR-PAG which did not spread to MRF. PES was accomplished by connecting the gold plated earrings to a pulse generator controlled by microcomputer (19). The PES consisted of 10 Hz, biphasic rectangular pulses with positive pulse width of 0.1 msec and amplitude of 10 PA (19). The PES leads were shielded and electrically isolated from the recording equipment. For noxious stimulation, the tail pinch (TP) procedure was used (1, 2, 15-17). The recording electrode (glass micropipette filled with 2 M NaCl and fast green) was driven in 1 pm steps by an hydraulic microdriver. The electrical events were amplified and simultaneously displayed on an oscilloscope and input to an audiomonitor (3,lS). Once a spontaneously active cell was observed, its electrical discharges were monitored over a 15-20 min period to “secure” stability prior to initiation of several random test procedures which consisted of 1) five
PAIN MODULATION
673
-T.P. v ,.-.-.PES
DRS
TIME (set) FIG. 2. Representative frequency histograms of PF “nociceptive-off’ cells before and during tail pinch (TP) application, dorsal raphe stimulation (DRS), pinnae electrical stimulation (PES). TP concomitant with DRS, and TP concomitant with PES in A, B, C, D, E and F,. res&tively.
min of spontaneous activity; 2) one min of spontaneous activity followed by TP for 15 set and an additional 3 to 4 min poststimulation activity; 3) one mm spontaneous activity followed by DRS for 1 min and an additional 3 min postDRS activity; 4) one min of spontaneous activity followed by 1 min DRS concomitant with 15 set TP delivered on the last 15 set of DRS followed by an additional 3 to 4 min of poststimulation recording; 5) one min spontaneous activity followed by PES for 1 min and an additional 3 to 4 min post PES activity; and 6) one min spontaneous activity followed by 1 min PES concomitant with 15 set TP delivered on the last 15 set of PES followed by an additional 3 to 4 min of poststimulation recording (Fig. 1). All data were stored on magnetic tape for off-line data evaluation. At the end of the experiment, the animals were overdosed with pentobarbital and perfused with 10% formalin and 3% potassium ferrocyanide. Then, 5 mA DC current for 5 set was passed through the DR electrode while 100 PA for 20 min was passed through the recording microbarrel to mark the location of the electrodes. The brains were removed and
stored in 10% formalin and later sectioned on a freezing microtome (650 pm) and stained with hematoxylin and eosin (15,16). Neuronal events were retrieved from the tapes and evaluated with a DEC MINC II minicomputer (15-17). The number of spikes/set and mean firing rate during each testing procedure were calculated and a frequency histogram was plotted. The percentage change of the spontaneous activity and the evoked activity following each treatment were calculated. Any change of 40% or greater from the control tiring rate was attributed to a significant treatment effect (17). RESULTS
A total of 47 PF neurons were recorded, 39 of them (39/47) were responsive to tail pinch (TP) in the following manner: 27 were excited (Fig. 1B) by TP; while the other 12 cells responded to TP with a decrease (Fig. 2B) of the spontaneous firing rate. Generally, the increased activity started immediately following TP and this increase in activity con-
674
QIAO, SKOLNICK TABLE
AND DAFNY
1
EFFECTS OF DORSAL RAPHE STIMULATION (DRS) AND PINNA ELECTRICAL STIMULATION (PES) ON THE SPONTANEOUS AND NOCICEF’TIVE DISCHARGES OF 27 PHYSIOLOGICAL IDENTIFIED “NOCICEPTIVE-ON” CELLS IN NUCLEUS PARAFASCICULARIS
Spontaneous
Discharges
Nociceptive
Decrease
Increase
No Change
22 9
3 2
2 16
DRS PES
Decrease
Discharges
Increase
No Change
2 2
7 9
18
16
TABLE 2 EFFECTS OF DRS AND PES ON THE SPONTANEOUS AND NOCICEPTIVE DISCHARGES PHYSIOLOGICAL IDENTIFIED “NOCICEF’TIVE-OFF” CELLS IN NUCLEUS PARAFASCICULARIS
Spontaneous Decrease DRS PES
9 1
Discharges
Increase
Nociceptive No Change
1 2
tinued throughout the stimulation period only and returned to baseline activity within 80-140 sec. These cells were classified as “nociceptive-on” cells (Fig. 1B). In those cells
demonstrating decrease in fiing rate following TP, this decrease also started immediately and outlasted the stimulation for 20-40 sec. These cells were classified as “nociceptiveoff’ cells (Fig. 2B). The unresponsive cells (8/47) were classified as “nonnociceptive” cells (17). As shown in Table 1, DRS suppressed both the spontaneous activity in 22 of 27 (82%) and the nociceptive input in 18/27 (670/o) of the “nociceptive-on” cells (Fig. 1). In contrast, PES suppressed the spontaneous discharges in 9127 (33%) and the nociceptive discharges in 16/27 (5%) of the observed cells. Thus, in general, DRS affected the spontaneous activity of the “nociceptive-on” cells studied more than did PES (p
Since the discovery that profound analgesia can be produced by either focal electrical stimulation of midbrain structures, including the DR (5, 14, 18,20), or local microin-
2 9
Decrease 11 3
OF 12
Discharges
Increase
No Change
0 8
I I
jection of morphine in these areas (21), a number of experiments have been carried out to clarify the structural and functional basis underlying the role of midbrain structures in pain modulation phenomena. Recently, it was reported that the responsiveness of single neurons to noxious stimuli in the PF can be modified by focal DRS (1, 2, 8, 17). The study reported here compares the relatively well known analgesic effects elicited by focal electrical DRS upon the noxious input at the PF levels (l-3, 9, 12, 20) against a different form of pain modulation produced by PES. The main finding of the present study is that PES of 0.1 msec, 10 Hz to 10 @A, which is below the threshold for induction of any gross behavioral reaction in anesthetized rats, nevertheless modified the spontaneous activity of single PF neurons. The startle threshold for producing the reaction in unanesthetized rats was measured at 30 PA (13). The same signal parameters in PES also modulated the noxious input elicited by TP of these cells in a manner similar to the effects induced by focal electrical DRS. In a previous experiment, a noxious stimulus (TP) and a nonoxious (NN) stimulus (brushing the contralateral leg) were used to identify the PF neurons physiologically. Four patterns of responses were obtained (17). Type A units responded with excitation only to TP and outlasted the stimutation for W-140 set; Type B units responded with excitation only to NN stimulus and outlasted the stimulation for 20-40 set; Type C units responded both to TP and to NN stimulus by excitation and outlasted the stimulation for 60-180 set, and Type D units responded to both stimuli by decreasing their fir& rates and outlasted the stimulation for 20-40 set (17). The recording presented in the present paper could be related either to Type A “nociceptive-on” cells (or “nociceptive specific”). Type D units “nociceptive-off” can be related to “nociceptive nonspecific” units. Finally, since the analgesic effects
675
PAIN MODULATION produced by focal DR stimulation are considered to be transmitted through distinct neural pathways (14), involving ascending and descending brain stem pathways (20), it is possible to assume that PES also exerts its effect of pain suppression at the PF level via activation of brain stem nuclei or via a diffuse noxious inhibitory control (DNIC) mech-
Supported in part by American Health Services, Inc. The authors gratefully acknowledge the technical help of P. Dougherty and
anism
the secretarial assistance of D. Parker for manuscript preparation.
(11). However,
whether
these
effects
are carried
via
applied 5-HT 1. Andersen, E.; Dafny, N. Microiontophorectically reduces responses to noxious stimulation in the thalamus. Brain Res. 241:176178; 1982. 2. Andersen, E.; Dafny, N. Dorsal raphe stimulation reduces responses of parafascicular neurons to noxious stimulation. Pain 15:323-332; 1983. 3. Andersen, E.; Dafny, N. An ascending serotonergic pain modulation pathway from the dorsal raphe nucleus to the parafasciculus nucleus of the thalamus. Brain Res. 269:57-67; 1983. 4. Andersson, S. A.; Ericson, T.; Holmgren, E.; Lindquist, G. Electroacupuncture: Effect of pain threshold measured with electrical stimulation of the teeth. Brain Res. 63:393-396; 1973. 5. Basbaum, A. I.; Fields, H. L. Endogenous pain control system: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7:3m338; 1984. 6. Blum, P. S. Control of sensory transmission by electrical stimulation within the caudal raphe nuclei of the cat. Exp. Neural. 72:570-581; 1981. 7. Chapman, I. D.; Pinnock, M. H.; Williams, D. C. The influence of different electrical stimulation in hexobarbital induced loss of righting reflex in rats. Acupunct. Electrother. Res. 7:16-26; 1982. 8. Dafny, N.; Gildenberg, P. Morphine effects on spontaneous, nociceptive, antinociceptive and sensory evoked responses of parafasciculus thalami units in morphine naive and morphine dependent rats. Brain Res. 323:1 I-20; 1984. 9. Gebhart, G. F. Opiate and opioid peptide effects on brain stem neurons: Relevance to nociception and antinociceptive mechanisms. Pain 12:93-140; 1982. 10. Kiinig, J. F. R.; Klippel, R. A. The rat brain: A stereotaxic atlas of the forebrain and lower parts of the brain stem. New York: R. E. Krieger Publishing Co. Inc.; 1970.
ascending clarified.
paths or descending
paths or both has yet to be
ACKNOWLEDGEMENTS
11. LeBars, D.; Dickenson, A. H.; Besson, J.-M. Diffise noxious inhibitory controls (DNIC). II. Lack of effect on nonconvergent neurones, supraspinai involvement and theoretical implications. Pain 6:305-327; 1979. 12. Liu, X.; Zhu, B.; Zhang, S. Relationship between electroacupuncture analgesia and descending pain inhibitory mechanism of nucleus raphe magnus. Pain 24:383-3%; 1986. 13. Malin, D. H.; Murray, J. B.; Crucian, G. P.; Schweitzer, F. C.; Cook, R. E.; Skolnick, M. Auricular microstimulation: naloxone-reversible attenuation of opiate abstinence syndrome. J. Biol. Psychiatry, in press; 1988. 14. Mayer, D. J. Analgesia produced by electrical stimulation of the brain. Prog. Neuropsychopharmacol. Biol. Psychiatry 8:557564; 1984. 15. Reyes-Vazquez, C.; Dafny, N. Microiontophoretically applied THIP effects upon nociceptive responses on neurones in the medial thalamus. Appl. Neurophysiol. 46:254-260; 1983. 16. Reyes-Vazquez, C.; Enna, S. J.; Dafny, N. The parafasiculus thalami as a site for mediating the antinociceptive response to GABAeraic drugs. Brain Res. 383:177-184: 1986. 17. Reyes-VazquezrC.; Prieto-Gomez, B.; Q&o, J.-T.; Dafny, N. Evidence for an ascending pain modulation pathway: dorsal raphe stimulation, 5-HT and morphine microiontophoresis effects on noxious and nonnoxious identified neurons in the medial thalamus of the rat. Submitted. 18. Reynolds, D. V. Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164:1969. 19. Skolnick, M. H.; Collard, C. D.; Hamilton, R. F.; HudsonHoward, L.; Hymel, C.; Wilson, 0.; Malin, D. H. Low current. electrostimulation produces naloxone-reversible analgesia in rats. Sot. Neurosci. Abstr. 13:1304; 1987. 20. Willis, W. D., Jr. Central nervous system mechanisms for pain modulation. Appl. Neurophysiol. 48: 153-165; 1985. _ 21. Yaksh, T. L.; Rudy, T. A. Narcotic analgesics: CNS sites and mechanisms of action is recorded by intracerebral injection techniques. Pain 24:229-359; 1978.
0361-9230/88 $3.00 + .OO
Dorsal Raphe and External Electrical Stimulation Modulate Noxious Input to Single Neurons in Nucleus Parafascicularis Thalami J.-T. QIAO, M. SKOLNICK
AND N. DAFNY’
University of Texas Medical School at Houston, Department of Neurobiology and Anatomy and Institute for Technology, Neurophysiology Research Center, Houston, TX 77030 Received
23 February 1988
QIAO, J.-T., M. SKOLNICK AND N. DAFNY. Dorsal raphe and external electrical stimulation modulate noxious input to single neurons in nucleus parafascicularis thalami. BRAIN RES BULL 21(4) 671-675, 1988.-Spontaneous discharges
and nociceptive responses of 47 parafascicularis thalami (PF) neurons were recorded extracellularly and comparisons were made between the effects of these discharges following focal dorsal raphe stimulation (DRS) and bilateral pinnal electrical stimulation (PES). Eighty-three percent of PF neurons (N=39) responded to noxious stimulus, about 6% of the PF responsive cells (N=27) were excited during noxious stimuli and thus categorized as “nociceptive-on” cells. The remaining cells. DRS and PES 31% (N=l2) were suppressed by the noxious stimuli, and were categorized as “nociceptive-off’ neurons as well as the noxious input to these cells, while the attenuated the spontaneous activity of the “nociceptive-on” spontaneous activity of the “nociceptive-off’ cells was suppressed only following DRS and not following PES. Moreover, PES displayed disinhibiting properties, namely, it reduced the suppression effects elicited by noxious input. In conclusion, it was demonstrated that both focal DRS and noninvasive PES were effective in modulating pain input to single neurons in the PF.
Thalamic neurons
Pain
Dorsal raphe
External electrostimulation
IN recent years, several studies have indicated that responsiveness to noxious stimuli can be modulated by focal brainstem electrical stimulation (5,12) without interference with other sensory and behavioral functions (6). Moreover, transcutaneous or transcranial stimulation in different forms (4, 7, 12) have been used for more than two decades clinically to moderate intractable pain. Recently, a form of external bilateral stimulation delivered noninvasively and at much lower current amplitude than previous modes has been reported (13,19). Thus, forms of stimulation, applied through electrodes attached to the pinnae, produce naloxone antagonizable, analgesic responses in rats. The mechanisms underlying this modulatory phenomenon are not yet understood. The objective of the present study is to compare the effects of focal electrical dorsal raphe stimulation (DRS) with noninvasive pinnal (ear) electrical stimulation (PES) at the level of the parafascicularis (PF) thalami neurons. The PF nucleus is one of several well studied subcortical sites impli-
‘Requests for reprints should be addressed
cated in pain perception, and since DRS has been well demonstrated to modulate noxious input to the PF (1, 2, 8, 17) this site was selected as the target site in the present study. It was observed that PES was as effective as focal DRS in modulating noxious input to PF at a single cell level. METHOD
Twenty-three male Sprague-Dawley rats weighing 180280 g were used as subjects. Three days prior to the experiment, gold plated, stainless steel earrings were inserted into each pinna (ear) of the animals to be later used as the eiectrodes for PES (19). The site for insertion is located by determining the highest local conductivity in the area of the vertex of the antihelix using an ampmeter with an internal signal. Electrode to electrode impedance was 8+0.4 kohms. On the experimental day, the rat was anesthetized with urethane (1.2 g/kg IP) and secured in a stereotaxic frame. Craniectomy was performed and the cortex underlying the
to N. Dafny.
671
612
QIAO, SKOLNICK u
1 A.
AND DAFNY
_T.P _..1.1.1.... DRS _.-.-._PES
TIME (set)
FIG. 1. Representative frequency histograms of PF “nociceptive-on” cells before and during tail pinch (TP) application, dorsal raphe stimulation (DRS), pinnae electrical stimulation (PES), TP concomitant with DRS, and TP concomitant with PES in A, B, C, D, E and F, respectively. PF was exposed (10,16). A hole (0.6 mm in diameter) was drilled above the DR in order to position a bipolar stimulation electrode (twisted 60 pm in diameter stainless steel teflon insulated wire) within this structure. The DR electrical stimulation was composed of 0.1 msec square pulses at 10 to 20 Hz at 50 PA. In previous experiments (2) the following procedure was established to identify the location of the stimulation electrode prior to the histological confirmation: Two electrodes were used, one implanted within the mesencephalic reticular formation (MRF) and the second within the DR-PAG area. Low current (0.1 mA; 1.O to 10 Hz) delivered to MRF elicits in PF neurons driven activity and general excitation, while 0.1 to 1.0 mA 1.0 to 10 Hz delivered to DR-PAG suppresses the spontaneous activity of the PF neurons. Currents higher than 1.0 mA delivered to DR-PAG elicit activity similar to that obtained following MRF stimulation, namely the current spread to MRF. In addition, electrode locations were con-
firmed later to be within the target sites. Thus, we used low-current (50 kA) delivery to DR-PAG which did not spread to MRF. PES was accomplished by connecting the gold plated earrings to a pulse generator controlled by microcomputer (19). The PES consisted of 10 Hz, biphasic rectangular pulses with positive pulse width of 0.1 msec and amplitude of 10 PA (19). The PES leads were shielded and electrically isolated from the recording equipment. For noxious stimulation, the tail pinch (TP) procedure was used (1, 2, 15-17). The recording electrode (glass micropipette filled with 2 M NaCl and fast green) was driven in 1 pm steps by an hydraulic microdriver. The electrical events were amplified and simultaneously displayed on an oscilloscope and input to an audiomonitor (3,lS). Once a spontaneously active cell was observed, its electrical discharges were monitored over a 15-20 min period to “secure” stability prior to initiation of several random test procedures which consisted of 1) five
PAIN MODULATION
673
-T.P. v ,.-.-.PES
DRS
TIME (set) FIG. 2. Representative frequency histograms of PF “nociceptive-off’ cells before and during tail pinch (TP) application, dorsal raphe stimulation (DRS), pinnae electrical stimulation (PES). TP concomitant with DRS, and TP concomitant with PES in A, B, C, D, E and F,. res&tively.
min of spontaneous activity; 2) one min of spontaneous activity followed by TP for 15 set and an additional 3 to 4 min poststimulation activity; 3) one mm spontaneous activity followed by DRS for 1 min and an additional 3 min postDRS activity; 4) one min of spontaneous activity followed by 1 min DRS concomitant with 15 set TP delivered on the last 15 set of DRS followed by an additional 3 to 4 min of poststimulation recording; 5) one min spontaneous activity followed by PES for 1 min and an additional 3 to 4 min post PES activity; and 6) one min spontaneous activity followed by 1 min PES concomitant with 15 set TP delivered on the last 15 set of PES followed by an additional 3 to 4 min of poststimulation recording (Fig. 1). All data were stored on magnetic tape for off-line data evaluation. At the end of the experiment, the animals were overdosed with pentobarbital and perfused with 10% formalin and 3% potassium ferrocyanide. Then, 5 mA DC current for 5 set was passed through the DR electrode while 100 PA for 20 min was passed through the recording microbarrel to mark the location of the electrodes. The brains were removed and
stored in 10% formalin and later sectioned on a freezing microtome (650 pm) and stained with hematoxylin and eosin (15,16). Neuronal events were retrieved from the tapes and evaluated with a DEC MINC II minicomputer (15-17). The number of spikes/set and mean firing rate during each testing procedure were calculated and a frequency histogram was plotted. The percentage change of the spontaneous activity and the evoked activity following each treatment were calculated. Any change of 40% or greater from the control tiring rate was attributed to a significant treatment effect (17). RESULTS
A total of 47 PF neurons were recorded, 39 of them (39/47) were responsive to tail pinch (TP) in the following manner: 27 were excited (Fig. 1B) by TP; while the other 12 cells responded to TP with a decrease (Fig. 2B) of the spontaneous firing rate. Generally, the increased activity started immediately following TP and this increase in activity con-
674
QIAO, SKOLNICK TABLE
AND DAFNY
1
EFFECTS OF DORSAL RAPHE STIMULATION (DRS) AND PINNA ELECTRICAL STIMULATION (PES) ON THE SPONTANEOUS AND NOCICEF’TIVE DISCHARGES OF 27 PHYSIOLOGICAL IDENTIFIED “NOCICEPTIVE-ON” CELLS IN NUCLEUS PARAFASCICULARIS
Spontaneous
Discharges
Nociceptive
Decrease
Increase
No Change
22 9
3 2
2 16
DRS PES
Decrease
Discharges
Increase
No Change
2 2
7 9
18
16
TABLE 2 EFFECTS OF DRS AND PES ON THE SPONTANEOUS AND NOCICEPTIVE DISCHARGES PHYSIOLOGICAL IDENTIFIED “NOCICEF’TIVE-OFF” CELLS IN NUCLEUS PARAFASCICULARIS
Spontaneous Decrease DRS PES
9 1
Discharges
Increase
Nociceptive No Change
1 2
tinued throughout the stimulation period only and returned to baseline activity within 80-140 sec. These cells were classified as “nociceptive-on” cells (Fig. 1B). In those cells
demonstrating decrease in fiing rate following TP, this decrease also started immediately and outlasted the stimulation for 20-40 sec. These cells were classified as “nociceptiveoff’ cells (Fig. 2B). The unresponsive cells (8/47) were classified as “nonnociceptive” cells (17). As shown in Table 1, DRS suppressed both the spontaneous activity in 22 of 27 (82%) and the nociceptive input in 18/27 (670/o) of the “nociceptive-on” cells (Fig. 1). In contrast, PES suppressed the spontaneous discharges in 9127 (33%) and the nociceptive discharges in 16/27 (5%) of the observed cells. Thus, in general, DRS affected the spontaneous activity of the “nociceptive-on” cells studied more than did PES (p
Since the discovery that profound analgesia can be produced by either focal electrical stimulation of midbrain structures, including the DR (5, 14, 18,20), or local microin-
2 9
Decrease 11 3
OF 12
Discharges
Increase
No Change
0 8
I I
jection of morphine in these areas (21), a number of experiments have been carried out to clarify the structural and functional basis underlying the role of midbrain structures in pain modulation phenomena. Recently, it was reported that the responsiveness of single neurons to noxious stimuli in the PF can be modified by focal DRS (1, 2, 8, 17). The study reported here compares the relatively well known analgesic effects elicited by focal electrical DRS upon the noxious input at the PF levels (l-3, 9, 12, 20) against a different form of pain modulation produced by PES. The main finding of the present study is that PES of 0.1 msec, 10 Hz to 10 @A, which is below the threshold for induction of any gross behavioral reaction in anesthetized rats, nevertheless modified the spontaneous activity of single PF neurons. The startle threshold for producing the reaction in unanesthetized rats was measured at 30 PA (13). The same signal parameters in PES also modulated the noxious input elicited by TP of these cells in a manner similar to the effects induced by focal electrical DRS. In a previous experiment, a noxious stimulus (TP) and a nonoxious (NN) stimulus (brushing the contralateral leg) were used to identify the PF neurons physiologically. Four patterns of responses were obtained (17). Type A units responded with excitation only to TP and outlasted the stimutation for W-140 set; Type B units responded with excitation only to NN stimulus and outlasted the stimulation for 20-40 set; Type C units responded both to TP and to NN stimulus by excitation and outlasted the stimulation for 60-180 set, and Type D units responded to both stimuli by decreasing their fir& rates and outlasted the stimulation for 20-40 set (17). The recording presented in the present paper could be related either to Type A “nociceptive-on” cells (or “nociceptive specific”). Type D units “nociceptive-off” can be related to “nociceptive nonspecific” units. Finally, since the analgesic effects
675
PAIN MODULATION produced by focal DR stimulation are considered to be transmitted through distinct neural pathways (14), involving ascending and descending brain stem pathways (20), it is possible to assume that PES also exerts its effect of pain suppression at the PF level via activation of brain stem nuclei or via a diffuse noxious inhibitory control (DNIC) mech-
Supported in part by American Health Services, Inc. The authors gratefully acknowledge the technical help of P. Dougherty and
anism
the secretarial assistance of D. Parker for manuscript preparation.
(11). However,
whether
these
effects
are carried
via
applied 5-HT 1. Andersen, E.; Dafny, N. Microiontophorectically reduces responses to noxious stimulation in the thalamus. Brain Res. 241:176178; 1982. 2. Andersen, E.; Dafny, N. Dorsal raphe stimulation reduces responses of parafascicular neurons to noxious stimulation. Pain 15:323-332; 1983. 3. Andersen, E.; Dafny, N. An ascending serotonergic pain modulation pathway from the dorsal raphe nucleus to the parafasciculus nucleus of the thalamus. Brain Res. 269:57-67; 1983. 4. Andersson, S. A.; Ericson, T.; Holmgren, E.; Lindquist, G. Electroacupuncture: Effect of pain threshold measured with electrical stimulation of the teeth. Brain Res. 63:393-396; 1973. 5. Basbaum, A. I.; Fields, H. L. Endogenous pain control system: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7:3m338; 1984. 6. Blum, P. S. Control of sensory transmission by electrical stimulation within the caudal raphe nuclei of the cat. Exp. Neural. 72:570-581; 1981. 7. Chapman, I. D.; Pinnock, M. H.; Williams, D. C. The influence of different electrical stimulation in hexobarbital induced loss of righting reflex in rats. Acupunct. Electrother. Res. 7:16-26; 1982. 8. Dafny, N.; Gildenberg, P. Morphine effects on spontaneous, nociceptive, antinociceptive and sensory evoked responses of parafasciculus thalami units in morphine naive and morphine dependent rats. Brain Res. 323:1 I-20; 1984. 9. Gebhart, G. F. Opiate and opioid peptide effects on brain stem neurons: Relevance to nociception and antinociceptive mechanisms. Pain 12:93-140; 1982. 10. Kiinig, J. F. R.; Klippel, R. A. The rat brain: A stereotaxic atlas of the forebrain and lower parts of the brain stem. New York: R. E. Krieger Publishing Co. Inc.; 1970.
ascending clarified.
paths or descending
paths or both has yet to be
ACKNOWLEDGEMENTS
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