Anesth Analg 2003;97:111-116
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Isoflurane Depresses Diffuse Noxious Inhibitory Controls in Rats Between 0.8 and 1.2 Minimum Alveolar Anesthetic Concentration
Steven L. Jinks, PhD*,
Joseph F. Antognini, MD*,
, and
Earl Carstens, PhD
*Department of Anesthesiology and Pain Medicine and
Section of Neurobiology, Physiology and Behavior, University of California, Davis
Address correspondence and reprint requests to Steven L. Jinks, PhD, Department of Anesthesiology TB-170, University of California, Davis, Davis, CA 95616. Address e-mail to sljinks{at}ucdavis.edu
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Abstract
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Diffuse noxious inhibitory control (DNIC) occurs when the response to a noxious stimulus is inhibited by a second, spatially remote noxious stimulus. The minimum alveolar anesthetic concentration (MAC) to suppress movement is not altered by a second remote noxious stimulus. We hypothesized that DNIC would be depressed in the peri-MAC range. Rats were anesthetized with isoflurane, and MAC was measured. We recorded dorsal horn neuronal responses to noxious thermal stimulation of the hindpaw, with or without concomitant supramaximal noxious mechanical stimulation of the tail or contralateral hindpaw. At 0.8 MAC, the tail clamp decreased neuronal responses 70% compared with control heat-evoked responses (from 1032 ± 178 impulses per minute to 301 ± 135 impulses per minute; P < 0.05). The tail clamp had no significant effect on neuronal responses at 1.2 MAC (from 879 ± 139 impulses per minute to 825 ± 191 impulses per minute; P > 0.05). Similarly, 1.2 MAC isoflurane significantly depressed DNIC elicited by hindpaw clamping. In another group, the cervical spinal cord was reversibly blocked by cooling to determine whether the inhibition was mediated supraspinally. With spinal cord cooling, the counterstimulus-evoked inhibition was not observed at 0.8 MAC. These results suggest that DNIC involves supraspinal structures and is present at sub-MAC isoflurane concentrations but is depressed at more than 1 MAC.
IMPLICATIONS: Diffuse noxious inhibitory control (DNIC) occurs when a noxious stimulus is perceived as being less painful when a second noxious stimulus is applied elsewhere on the body. DNIC is present in anesthetized animals, although how anesthesia affects it is unknown. We found that isoflurane depressed DNIC in the transition from 0.8 to 1.2 minimum alveolar anesthetic concentration, suggesting that DNIC is depressed in the anesthetic range needed to suppress movement.
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Introduction
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Diffuse noxious inhibitory control (DNIC) describes inhibition of activity in convergent or wide dynamic range (WDR)-type nociceptive spinal neurons that is triggered by a second, spatially remote noxious stimulus (1,2). This phenomenon is thought to underlie the principal of counterirritation to reduce pain (3), whereby "one pain masks another" (2). In humans, remote noxious stimuli can inhibit both the perceived intensity of pain and the magnitude of a concomitant RIII reflex, a nociceptive motor reflex elicited by graded noxious electrical stimulation (4,5). In anesthetized rats, remote noxious stimuli also depress certain nociceptive withdrawal reflexes (6), although other nociceptive reflexes can be facilitated, possibly to promote escape from the offending stimulus (7,8), suggesting that DNIC-induced depression of dorsal horn nociceptive processing is not always strictly related to motor reflex responses. However, anesthetic requirements, as measured by the minimum alveolar anesthetic concentration (MAC) necessary to produce immobility to a noxious stimulus, are apparently not altered by noxious counterstimulation (9). That is, once a supramaximal stimulus is applied, a second noxious stimulus does not alter anesthetic requirements to prevent movement. Such an apparent lack of counterstimulus effect might be due to anesthetic depression of DNIC in the peri-MAC range. We hypothesized that DNIC observed in rats anesthetized at a sub-MAC concentration of isoflurane would be depressed at concentrations more than 1 MAC.
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Methods
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This study was approved by the University of California, Davis animal care and use committee. Adult male Sprague-Dawley rats (n = 10) were placed in a plastic chamber, and isoflurane 4%–5% was delivered until the animals were anesthetized. On removal, isoflurane (2%–3%) was delivered via mask, and a tracheotomy was performed to permit insertion of a tracheal tube and mechanical ventilation. Inspiratory and expiratory gases were monitored with a calibrated anesthetic analyzer (Datex, Helsinki, Finland) that sampled alveolar gases from the proximal end of the tracheotomy tube. A jugular vein was cannulated to provide for fluid administration and pancuronium 0.3–0.5 mg · kg-1 · h-1. Blood pressure was measured from a cannula placed in a carotid artery. Rectal temperature was measured and maintained at 37.0°C ± 0.6°C with a heating lamp. A lumbar laminectomy was performed. After the surgical procedures, MAC was determined as previously described (10). In brief, the end-tidal isoflurane was adjusted to approximately 1.2% and equilibrated for 15–20 min, and a hemostat was applied to the mid portion of the tail for 60 s while we watched for gross purposeful movement. Depending on the response, the isoflurane was increased or decreased 0.2% and equilibrated for 15–20 min, and the tail clamp was applied again. This process continued until two isoflurane concentrations were found that just permitted and prevented movement. The average of these two values was the MAC for that animal.
The rat was stabilized in a stereotaxic frame by placing spinal clamps above and below the laminectomy and by securing the head with ear bars. The dura was removed, and a warm agar solution was applied over the spinal cord and allowed to solidify. A tungsten electrode (impedance, 
13–15 M
; FHC, Bowdingham, ME) was inserted into the lumbar dorsal horn by using a microdrive (Kopf, Tujunga, CA). The signal was filtered (0.3–3 kHz), amplified, and passed into two computers that digitized the signal and saved the responses to a hard drive. One computer recorded the raw filtered and amplified signal (Chart; ADI, Grand Junction, CO) while the other computer saved each action potential (11). We sought neurons that responded to pressure, pinching, and thermal stimulation of the left hindpaw and were therefore classified as WDR-type neurons. Once a unit was isolated, the left hindpaw was taped to the thermal device, which consisted of a feedback-regulated Peltier thermode (0.42 cm2). The thermode contacted the glabrous portion of the hindpaw.
The anesthetic was adjusted to 0.8 MAC (by using each animal’s own MAC), and the response to a 15-s thermal stimulus (51°C) was recorded (Fig. 1A). In general, two or three responses were obtained for each experimental condition, with an interstimulus interval of 5 min, alternating between control and counterstimulation procedures. Five minutes later the process was repeated, except that 5 s before application of the thermal stimulus, a hemostat was applied 5 cm from the proximal end of the tail (at a force equal to that used to determine MAC) and left in place for 15 s (Fig. 1A). In seven of these rats, we also used a clamp applied to the contralateral hindpaw as the counterstimulus. The isoflurane was adjusted to 1.2 MAC and allowed to equilibrate for 15–20 min, and the paradigm was repeated. The order in which isoflurane MACs were delivered was switched from experiment to experiment.
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Figure 1. Experimental paradigm. A, Action potentials were recorded before and after application of the thermal stimulus (temperature tracing). The number of action potentials during the 60-s period after the initiation of the thermal stimulus represents the 60-s response (R60). After collection of control data, the stimulus was repeated in the presence (15 s) of a counterstimulus (tail clamp or contralateral hindpaw clamp applied 5 s before thermal stimulus application). B, Evoked potentials (EPs) were elicited by stimulating the sciatic nerve and recording from needle electrodes placed between the skull and cerebral cortex; the EPs were averaged over 512 stimuli and repeated. Three examples show the depression of the EP with progressive cooling of the cervical spinal cord. The spinal cord temperatures (dorsal, TD; and ventral, TV) are shown in each example.
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We sought to establish whether any inhibitory process was dependent on supraspinal structures, an expected characteristic of DNIC (7). In a separate group of rats (n = 10), the surgical procedures were performed as described above except that a cervical laminectomy was performed to permit placement of a custom-made cooling probe on the cervical spinal cord at C2. This probe was wedge shaped, with a concave area (0.3 cm2) at the tip. The probe was hollow, and inflow and outflow tubes were placed into it to permit pumping of dry ice-cooled ethanol through it. We performed preliminary experiments to confirm that this device was capable of blocking axonal conduction (Fig. 1B). In brief, we placed small temperature probes on the dorsal and ventral surfaces of the cord and measured somatosensory evoked potentials (EPs) from the cortex. The EPs were obtained by using a NeuroTrac electroencephalogram/EP machine (Conshohocken, PA) with the stimuli applied to an exposed sciatic nerve, which was bathed in mineral oil. The cord was cooled, and we determined at what dorsal cord temperature the EPs were lost.
The stimulus paradigm was repeated before, during, and after spinal cord cooling. We measured the dorsal spinal cord temperature and adjusted it to 1 ± 1°C, which was well below the dorsal temperature at which EPs were depressed (9°C–12°C).
The two or three neuronal responses obtained at each experimental condition were averaged and are reported as the number of action potentials in the 60 s after initiation of the thermal stimulus (Fig. 1A). Data are presented as mean ± SE unless otherwise noted. The neuronal responses were compared by using repeated-measures analysis of variance followed by a paired Student’s t-test with a Bonferroni correction. Significance was set at P < 0.05.
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Results
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Isoflurane MAC was 1.2% ± 0.1%. The neurons, all isolated at 0.8 MAC, were classified as WDR neurons in that they responded to increasing stimulus intensity with an increased number of action potentials. Individual examples of evoked responses are shown in Figures 2 and 3, and summary data are shown in Figure 4.
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Figure 2. Individual examples of isoflurane effects (A) and cervical spinal cooling (B) on diffuse noxious inhibitory controls. Peristimulus-time histograms (bin width, 1 s) are shown. In (A), a noxious thermal stimulus (51°C) applied to the left hindpaw evoked a neuronal response; the isoflurane was at 0.8 minimum alveolar anesthetic concentration (MAC) in the first and third panels. When a counterstimulus (tail or right hindpaw [HP] clamp) was applied, the neuronal response to the thermal stimulus was inhibited. When the isoflurane was increased to 1.2 MAC (second and fourth panels), the counterstimuli did not inhibit the response. In (B), the response to noxious heat (51°C) was inhibited by the tail clamp at 0.8 MAC before the upper cervical spinal cord was cooled (left panel), but during cooling, the response to heat was enhanced and the tail clamp no longer inhibited the heat-evoked response (middle panel). After the cord was rewarmed, the counterstimulus-induced inhibition returned (right panel).
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Figure 3. Individual example of action potentials during noxious thermal stimulation applied to the hindpaw (temperature shown between [B] and [C]). Note that, at 0.8 minimum alveolar anesthetic concentration (MAC) isoflurane, the number of evoked action potentials in (A) in the absence of noxious counterstimulation was considerably greater than that in (B) with noxious counterstimulation (tail clamp applied for 15 s). The tracings in (C) and (D) show that at 1.2 MAC, the tail clamp had a much smaller depressant effect on the response to noxious thermal stimulation.
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Figure 4. Summary data (mean ± SE) with significance values. In (A), the effect of the tail clamp on evoked neuronal activity is shown. The tail clamp significantly inhibited the neuronal response to the thermal stimulation of the left hindpaw at 0.8 minimum alveolar anesthetic concentration (MAC) (P = 0.0032), but at 1.2 MAC, heat-evoked responses were not inhibited. Also, the response at 1.2 MAC without the tail clamp was three times as great as the response at 0.8 MAC with the tail clamp (P = 0.002). In (B), a clamp applied to the right hindpaw significantly inhibited the neuronal response to thermal stimulation of the left hindpaw at 0.8 MAC (P = 0.001), and there was less inhibition at 1.2 MAC (P = 0.019). In (C), cooling the spinal cord removed the inhibition resulting from the counterstimulus (tail clamp). Note also that the response to thermal stimulation was increased during spinal cord cooling (P = 0.016 compared with the 0.8 MAC control in [C]); this was presumably related to removal of supraspinal tonic inhibition.
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In the first group, 10 WDR neurons were studied, and they reliably responded to noxious thermal stimulation. The mean recording depth was 342 ± 208 µm. The neurons generally had low spontaneous activity, even at 0.8 MAC (17 ± 22 impulses per minute; mean ± SD); at 1.2 MAC, spontaneous activity tended to be further depressed (6 ± 5 impulses per minute), although, compared with the 0.8 MAC value, this did not reach statistical significance. At 0.8 MAC, neuronal responses to the thermal stimulus were significantly inhibited by the tail clamp (Figs. 2–4): from 1032 ± 178 impulses per minute (no clamp) to 301 ± 135 impulses per minute (with tail clamp) (P < 0.05). This inhibitory response was abolished at 1.2 MAC—from 879 ± 139 impulses per minute (no clamp) to 825 ± 191 impulses per minute (with tail clamp) (P > 0.05)—although control responses to heat were not significantly depressed at 1.2 MAC compared with 0.8 MAC. Application of a clamp to the contralateral hindpaw (n = 7) at 0.8 MAC inhibited the neuronal response to noxious heat to an extent similar to that produced by the tail clamp (Figs. 2A and 4B ). At 1.2 MAC, the hindpaw clamp had no significant effect on the 60-s neuronal response to thermal stimulation, and the inhibition of the response produced by the hindpaw clamp was significantly greater at 0.8 MAC than at 1.2 MAC (Fig. 4) (P < 0.05; paired Student’s t-test). However, at 1.2 MAC, during the period of clamp application, hindpaw counterstimulation significantly decreased the neuronal response (from 401 ± 275 impulses per 10 s to 192 ± 225 impulses per 10 s; P < 0.05; paired Student’s t-test). In contrast, the first 10 s of the heat-evoked response was not significantly depressed by the tail clamp at 1.2 MAC.
Ten WDR neurons were studied in the second group that underwent spinal cord cooling. The mean recording depth was 238 ± 88 µm. Before cooling, the thermal stimulus evoked a significant neuronal response at 0.8 MAC (Figs. 2B and 4C), and this was inhibited by the tail clamp. Once the cervical spinal cord was cooled, the evoked response was increased significantly (the cold-block response compared with the pre-cold response in Figs. 2 and 4 ). Furthermore, tail clamping did not significantly inhibit the response as it had before cooling. However, the trend, showing a slight decrease in response during tail clamp (approximately 10%; Figs. 2B and 4C), suggested a small intraspinal contribution to the counterstimulus-induced inhibition. The spinal cord was allowed to return to body temperature, and recovery was noted: 1454 ± 534 impulses per minute (no clamp) and 1005 ± 460 impulses per minute (with tail clamp) (P < 0.01; paired Student’s t-test).
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Discussion
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The main finding of this study was that DNIC was depressed by isoflurane anesthesia at a concentration around 1 MAC, which prevented purposeful movements. Isoflurane anesthesia abolished DNIC elicited from the tail and significantly depressed DNIC elicited from the contralateral hindpaw. The depression of DNIC at 1.2 MAC isoflurane was not accompanied by a change in noxious heat-evoked responses, consistent with our prior studies (12). Cooling the spinal cord depressed DNIC produced by a tail clamp, indicating that supraspinal structures are largely involved in DNIC, as previously reported (2,13,14).
DNIC has been investigated primarily in rats anesthetized with sub-MAC concentrations of halothane or barbiturates (1,2,6–8,14,15), and effects of increased anesthetic concentration were generally not tested. These findings are the first to investigate DNIC by using isoflurane anesthesia and to show a reduction or abolition of DNIC at concentrations larger than 1 MAC. Prior studies have shown that DNIC may be accompanied by a depression (6) or facilitation (7,8) of nociceptive reflexes. Our results show that DNIC-induced inhibition of nociceptive dorsal horn neurons is present at sub-MAC isoflurane concentrations that presumably would have permitted movement.
The control neuronal responses (i.e., in the absence of a counterstimulus) to noxious heat were minimally affected when the isoflurane concentration was increased from 0.8 to 1.2 MAC, confirming our recent report (12) and implying that isoflurane must be acting at spinal sites ventral to the dorsal horn (e.g., directly on motoneurons) to produce immobility. Furthermore, our finding that neuronal responses at 1.2 MAC are nearly triple the responses at 0.8 MAC in the presence of a counterstimulus (Fig. 4A), despite the likelihood that movement would have occurred in the latter instance but not the former, is additional evidence that there is an apparent disconnection between dorsal horn neuronal activity and motor responses.
During surgery, patients are subjected to a variety of noxious stimuli that are sometimes spatially remote. Although anesthetic requirements are unchanged with two supramaximal noxious stimuli (as compared with just one) (9), it is unclear whether two or more submaximal noxious stimuli applied simultaneously require the same anesthetic level as is required for one supramaximal noxious stimulus. The presence of DNIC suggests that, in fact, anesthetic requirements might be altered in such a situation. An animal receiving a noxious stimulus that is just barely supramaximal would require 1 MAC anesthesia to prevent movement 50% of the time. Assuming that a stimulus with half this intensity was applied at 0.6 MAC and the animal moved, what would happen if a second noxious stimulus at one-quarter maximal intensity was applied to a different part of the animal? One could envisage that, because of DNIC, the animal would not move because of the diminished nociceptive throughput. Furthermore, whether DNIC will be operative in this setting likely depends on the timing of the various stimuli, because DNIC can last for seconds to minutes. The spinal cord is the site where several anesthetics, such as isoflurane, halothane, and thiopental, ablate movement to a supramaximal stimulus (16–18). Although DNIC is mediated largely by supraspinal structures, DNIC might nevertheless modulate movement at sub-MAC anesthetic concentrations.
Dickenson and Le Bars (19) reported that spinothalamic tract cells were inhibited by remote noxious stimuli, consistent with DNIC. Such a depression of spinothalamic tract cells would presumably decrease pain perception by blunting ascending noxious-evoked impulses to the brain. Human studies clearly document decreased pain perception of a noxious stimulus when a second noxious stimulus is applied elsewhere on the body (4,5). Memory and consciousness are ablated at 0.3–0.5 MAC (20), a range in which DNIC is operative. It is possible that anesthetic requirements for amnesia and unconsciousness might be altered when two stimuli are present as compared with when one stimulus is present, because DNIC would diminish ascending impulses to the brain.
The hindpaw counterstimulus inhibited the heat-evoked neuronal response only during the period of its application, with no effect on the afterdischarge, whereas the tail clamp was effective during and after its application. The strength of DNIC is reported to vary with the site of counterstimulation (19). The differences between the tail clamp data and the hindpaw clamp data in this study might reflect this regional variation. In any case, DNIC was depressed or abolished by isoflurane concentrations just above MAC.
The pathway mediating DNIC involves a spino-bulbo-spinal loop (2,14,21), as well as smaller contributions from propriospinal pathways, which, however, appear to play a lesser role (13). Spinal WDR neurons relay signals via ventrolateral pathways (15) to the caudal medulla, including the subnucleus reticularis dorsalis, which in turn connect to descending inhibitory projections (via the dorsal lateral funiculus) to dorsal horn neurons throughout the spinal cord (21). Our findings confirm an important supraspinal loop in DNIC, because inhibitory effects of remote noxious stimulation were significantly attenuated during reversible cold block of the cervical spinal cord. Furthermore, during cold block, neuronal responses to noxious heat were enhanced, consistent with previous studies (22), indicating that such neurons are under tonic supraspinal inhibition. It is not clear at what site(s) isoflurane acts to block DNIC. Possibilities include a supraspinal site where isoflurane could influence descending modulatory pathways or a spinal level where isoflurane could alternatively block ascending nociceptive transmission or reduce descending inhibition acting on WDR neurons. Thus, although our results clearly demonstrate a depressant effect of isoflurane anesthesia on DNIC, further studies are needed to precisely identify the site of action underlying this effect.
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Acknowledgments
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Supported in part by National Institutes of Health Grants GM 57970 and GM61283 (JFA) and by a National Research Service Award (NS43935-01) (SLJ).
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Accepted for publication February 25, 2003.
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Abstract
Introduction
