Anesth Analg 2004;99:1413-1419
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000135635.32227.DA
ANESTHETIC PHARMACOLOGY
Isoflurane Depresses Windup of C Fiber-Evoked Limb Withdrawal with Variable Effects on Nociceptive Lumbar Spinal Neurons in Rats
Steven L. Jinks, PhD*,
Joseph F. Antognini, MD*,
,
Robert C. Dutton, MD
,
Earl Carstens, PhD, and
Edmond I Eger, II, MD
*Department of Anesthesiology and Pain Medicine, and
Section of Neurobiology, Physiology, and Behavior, University of California, Davis; and
Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California
Address correspondence to Joseph F. Antognini, MD, TB-170, Department of Anesthesiology and Pain Medicine, University of California, Davis, One Shields Dr., Davis, CA 95616. Address e-mail to jfantognini{at}ucdavis.edu
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Abstract
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Windup is a progressive increase in responses of nociceptive spinal cord neurons to repeated electrical C fiber stimulation. We hypothesized that isoflurane would depress windup at approximately the minimum alveolar anesthetic concentration (MAC) required to suppress purposeful movement in response to noxious stimulation. We recorded windup responses in single lumbar spinal neurons (n = 17) to a series of 15 repetitive electrical stimuli delivered at 1 Hz to the hindpaw at C fiber strength; hindpaw withdrawal force was simultaneously recorded. The total number of action potentials per 15 stimuli (mean ± SEM as a percentage of each neuron’s maximal response) was 83% ± 5%, 84% ± 5%, 67% ± 7%, and 57% ± 8% at 0.7, 0.9, 1.1, and 1.4 MAC, respectively. The 0.9 and 1.1 MAC values differed significantly from each other, whereas the 0.7 and 0.9 MAC values differed from the 1.4 MAC value (P < 0.05). The reduced firing was attributed to a depression of the initial C fiber-evoked responses in most units, and a reduction in windup slope over the initial 5 stimuli in 6 units. Muscle force was 67%, 11%, and 4% of the 0.7 MAC value at 0.9, 1.1, and 1.4 MAC, respectively. Isoflurane depressed excitability and variably affected windup of lumbar spinal cord neurons, while uniformly depressing windup of limb withdrawals in a concentration-dependent manner.
IMPLICATIONS: Isoflurane may exert part of its antinociceptive action by depressing spinal cord neuronal excitability and windup, an action that might occur at least partly at the N-methyl-D-aspartate receptor.
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Introduction
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Windup is the progressive increase in responses of nociceptive spinal cord neurons to repeated electrical C fiber stimulation (1,2). The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor mediates at least part of windup, because it is depressed or abolished by NMDA antagonists (3–5). Windup presumably reflects temporal summation at synapses between nociceptors and spinal neurons, and as such is likely to be an important neural mechanism underlying the temporal summation of pain sensation to repetitive noxious stimuli (6). We recently reported that increasing the frequency of repetitive electrical stimulation of the rat’s tail resulted in a progressive increase in the concentration of isoflurane necessary to prevent evoked movements (7). That is, isoflurane MAC, the minimum alveolar anesthetic concentration needed to prevent organized movement in response to a supramaximal noxious stimulus in 50% of subjects, is influenced by temporal summation. Moreover, the increase in anesthetic requirement at higher (but not lower) stimulus frequencies was reversed by administration of MK-801, an NMDA receptor antagonist (7).
These data suggest that NMDA receptor-mediated temporal summation influences anesthetic requirements. Because isoflurane can block NMDA receptors (8), it may be predicted that isoflurane reduces windup and thereby impairs temporal summation of movement resulting from repetitive noxious stimuli. One study has reported a weak effect of isoflurane on central temporal summation in humans (9), but there are no studies of inhaled anesthetic effects on neuronal windup. In the present study, we have examined the effect of isoflurane on C fiber-evoked neuronal windup, as well as the force of simultaneously recorded limb withdrawals, in rats. We hypothesized that isoflurane would depress windup of the neuronal responses as well as the motor response.
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Methods
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The animal care and use committee at the University of California, Davis approved this study. Nine Sprague-Dawley rats (400–500 g) were anesthetized with isoflurane/balance O2 in a chamber. A 14-gauge catheter was placed in the trachea (tracheostomy) and mechanical ventilation commenced and adjusted to maintain end-tidal carbon dioxide at 30–40 mm Hg; isoflurane was maintained at approximately 2% during the surgical procedures. A jugular vein and carotid artery were cannulated for fluid administration and arterial blood pressure measurement, respectively. Mean arterial blood pressure was maintained >70 mm Hg with infusion of isotonic fluids. The rectal temperature was measured and maintained at 37° ± 1°C using a warming pad and a light. A lumbar laminectomy was performed to permit measurement of single unit activity. MAC for each rat was determined as previously described (10). In brief, the end-tidal isoflurane concentration was measured using a calibrated agent analyzer. After 15 min of equilibration, a hemostat was applied to the tail (1 min) and the rat was observed for gross, purposeful movement. The isoflurane was increased or decreased 0.2% depending on the initial response and equilibrated at the new concentration. This process continued until two isoflurane concentrations were found that just permitted and just prevented movement; MAC was the average of these. Each rat’s individual MAC was used to define the concentrations applied during the subsequent neurophysiological recordings.
The rats were placed in a stereotaxic frame using vertebral clamps placed rostral and caudal to the laminectomy. The dura was split and warm agar was poured onto the spinal cord. A small portion of the agar was removed and a multielectrode shank was advanced into the lumbar spinal cord (L5-6) using a hydraulic microdrive. The electrode shank was obtained from the University of Michigan as part of a program (Center for Neural Communication Technology) supported by the National Institutes of Health (http://www.engin.umich.edu/facility/cnct/). The tapered shank was 5 mm long (width near tip: 33 µm) with 16 iridium recording electrodes located 50 µm apart along the distal 1 mm of the tip (Fig. 1). The resistance of the electrodes varied from 1.1 to 2.6 M
. We searched for neurons that responded to a noxious stimulus (pinch) applied to the hindpaw. Because the shank had multiple recording electrodes, we were often able to record activity of different neurons simultaneously. The depth of each neuron was estimated from the position of the electrode relative to the insertion depth of the shank. We classified neurons as either wide-dynamic-range (WDR) neurons in that they responded to increasing stimulus intensity with increasing number of action potentials, or nociceptive-specific (NS) in that they responded only to noxious stimulation (e.g., pinching with forceps). We also found neurons that were inhibited (their spontaneous activity decreased) in response to noxious pinch and electrical C fiber stimulation. These neurons were classified as "winddown" neurons. All neurons were searched and isolated at 0.9 MAC. In seven rats, we placed tape around the ankle of a hindpaw and connected this to a force transducer (FT03; Grass Inc., Astro-Med, West Warwick, RI) to measure isometric withdrawal force of the hindlimb that was ipsilateral to electrical stimulation (10).
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Figure 1. Drawing of multielectrode shank used to record neuronal action potentials. The tip was tapered and was 5 mm long (width near tip: 33 µm). The distal 1 mm of the recording tip (magnified) had 16 sites that were 50 µm from each other. The shank was attached to a custom-made cable that attached to the recording system.
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Two needle electrodes were placed into an area of the hindpaw skin spanning the mechanical receptive fields of isolated neurons recorded simultaneously. Electrical current was passed using a stimulus paradigm typically used in windup studies (15 stimuli, 40–50 V, 0.5-ms duration, 1 Hz) and neuronal responses were recorded by downloading the raw action potentials (after amplification; Tucker-Davis Technologies, Alachua, FL) to a computer using Chart 5.0 (AD Instruments, Colorado Springs, CO). This process was performed at 0.7, 0.9, 1.1, and 1.4 MAC, after allowing 15–20 min to elapse at each new MAC level.
The number of action potentials occurring after each electrical stimulus was counted using the Spike Histogram program of Chart 5.0. Action potentials occurring in the first 50 ms after each electrical stimulus were excluded, because they likely represented A fiber rather than C fiber activation (2). We performed an "area under the curve" analysis by summing all the action potentials across 15 electrical stimuli. The data were normalized by comparing the total number of action potentials for each neuron at each anesthetic concentration to the maximal number of action potentials generated by the neuron (which was usually at 0.7 MAC). The effect of isoflurane on windup was also assessed using linear regression analysis to calculate the slope of windup over the initial five stimuli under each anesthetic condition. Criteria for depression of neuronal windup were that the slope was reduced progressively with increasing isoflurane concentration, and that the slope was maximally reduced by 
50%. Muscle force after each stimulus was summed and compared across anesthetic concentrations.
All data were expressed as mean and standard error. The normalized action potential data and muscle force data were compared across all MAC levels using a two-factor analysis of variance followed by the Fisher’s least significance differences test. The sub-MAC normalized action potential data (average of 0.7 and 0.9 MAC data) and supra-MAC data (average of 1.1 and 1.4 MAC data) were compared with a paired t-test. Significance was assumed with a P < 0.05.
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Results
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The isoflurane MAC was 1.2% ± 0.1%. We studied windup in 20 neurons in 9 rats, but 3 neurons were excluded because of incomplete data, e.g., inability to consistently record action potentials. The remaining 17 neurons were 720 ± 110 µm below the surface of the spinal cord; 5 neurons were characterized as WDR, 11 as NS, and 1 neuron was not classified. The responses of the WDR neurons tended to be greater than the responses of NS neurons, but this was not statistically significant so the data were pooled. Winddown neurons (n = 4; depth: 685 ± 190 µm) were inhibited by noxious pinch and electrical C fiber stimulation at sub-MAC isoflurane concentrations. Winddown neurons typically had more spontaneous activity than windup neurons.
Windup was characterized by a progressive increase in the number of action potentials evoked by each successive C fiber stimulus until a plateau was reached, usually after 5–8 stimuli. The example in Figure 2A shows spike trains to demonstrate the progressive increase in C fiber discharge over the initial stimulus trials at 0.7 MAC (windup), with a concentration-dependent delay and diminution in C fiber-evoked responses at progressively larger isoflurane concentrations. The depressant effect of isoflurane manifested in different ways: as a reduction in the slope of the initial part of the windup curve, a downward parallel shift in the windup curve, or a combination of these. Figure 2B illustrates a concentration-dependent reduction in the initial slope of windup over the first 7–10 stimulus trials. Such concentration-dependent reductions in the initial windup slope (by 50%) were observed in 6 units. Figure 2C illustrates a parallel rightward shift in the windup curve at supra-MAC isoflurane concentrations. This pattern was observed in most of the remaining units, whereas a few showed a parallel shift and slope reduction. The data are summarized in Figure 3A, which plots mean responses of all 17 units at each isoflurane concentration against stimulus number, as well as the mean and SEM for the sub-MAC (average of 0.7 and 0.9 MAC) and supra-MAC (average of 1.1 and 1.4 MAC) data. Overall, there was a concentration-dependent reduction in the initial C fiber-evoked responses, as well as a downward shift in the windup curves at 1.1 and 1.4 MAC. Figure 3B plots the mean number of action potentials (normalized to each unit’s maximal firing rate—usually at 0.7 MAC) evoked by all 15 C fiber stimuli. Isoflurane depressed motor responses to repetitive C fiber stimulation. Mean withdrawal force is plotted against stimulus number in Figure 3C to show windup during repetitive stimulation at 0.7 MAC, and a delayed response and reduction in slope of the windup curves at 0.9 and 1.1 MAC. Motor responses were largely reduced at 1.1 MAC and almost totally abolished at 1.4 MAC.
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Figure 2. Windup in lumbar spinal cord neurons and effects of isoflurane. A, Raw tracing of action potentials and hindlimb withdrawal force. An electrical stimulus (40 V at 1 Hz) was applied to the hindpaw (timing indicated by stimulus artifacts) while recording from a lumbar dorsal horn neuron. Each successive stimulus elicited a progressive increase in the number of action potentials (windup). As the anesthetic was increased from 0.7 to 1.4 minimum alveolar anesthetic concentration (MAC), fewer action potentials occurred, especially in the first 5 stimuli. The total number of action potentials for all 15 stimuli overlies each tracing. The withdrawal force is below each action potential tracing; force decreased as the anesthetic was increased. B, Example of unit exhibiting isoflurane-sensitive windup. Graph plots number of action potentials versus stimulus number to show the progressive increase in response over the first 7 stimuli (windup) at 0.7 MAC. The initial slope of windup was progressively reduced with increasing isoflurane concentration. C, Example of a unit showing a parallel rightward shift in windup curves at supra-MAC isoflurane concentrations (format as in B).
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Figure 3. Summary data. A, Mean neuronal responses in 9 rats at 0.7, 0.9, 1.1, and 1.4 minimum alveolar concentration (MAC), as well as the mean and standard error (SE) of the sub-MAC and supra-MAC values. With each subsequent stimulus the number of action potentials increased although, at 0.7 and 0.9 MAC, the response leveled off beyond stimulus numbers 3–4. The sub-MAC responses (normalized) were significantly greater than the supra-MAC responses. B, Neuronal responses (as a percent of maximal response) are shown for all 15 stimuli as a function of MAC. C, The motor response (mean, SE) after each stimulus is shown as a function of anesthetic concentration. There is a significant depression, especially between 0.9 and 1.1 MAC. #P < 0.05 compared with 0.7 MAC; *P < 0.05 compared with 0.9 MAC; **P < 0.05 compared with 0.7 and 0.9 MAC.
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In four neurons that exhibited inhibitory responses to noxious pinch, we observed "winddown" that was significantly depressed by isoflurane (Fig. 4). At 0.7 and 0.9 MAC, the initial C fiber stimuli elicited responses, which progressively decreased with each successive electrical stimulus to below the prestimulus spontaneous firing (Fig. 4A, middle tracings). At 1.1 MAC, a larger number of repetitive electrical stimuli were required before the response subsided, whereas at 1.4 MAC the evoked responses did not start to decline until the final 3–4 stimuli in the series (Fig. 4A). Mean responses of the 4 units exhibiting winddown are plotted in Figure 4B against stimulus number. The spontaneous firing rates were not different at sub-MAC and supra-MAC isoflurane concentrations. At sub-MAC isoflurane concentrations, there was a rapid decline in the C fiber-evoked excitatory responses, suggesting inhibition of these neurons. At supra-MAC concentrations, however, C fiber stimulation less effectively inhibited the units suggesting disinhibition. Furthermore, there was a significant decrease in the rate of decline of responses (i.e., responses to stimuli 1–5 were significantly different between sub-MAC and supra-MAC anesthetic concentrations, P < 0.05, two-factor analysis of variance), which exhibited a reduction below the baseline spontaneous firing rate only during the final stimuli in the series (Fig. 4B).
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Figure 4. Inhibitory responses. A, Raw tracing of action potentials and hindlimb withdrawal force at 0.7–1.4 minimum alveolar anesthetic concentration (MAC). The top tracings show a simultaneously recorded neuron with windup; the transition from 0.7 to 1.4 MAC abolished windup. The middle tracings show a neuron with winddown. Note that the initial electrical stimuli caused windup but winddown then occurred; at 1.1–1.4 MAC, the initial windup was increased in magnitude and duration compared with the windup at 0.7 MAC. The bottom tracings show the corresponding motor response. B, The number of action potentials per stimulus was averaged for 0.7 and 0.9 MAC (sub-MAC) and for 1.1 and 1.4 MAC (supra-MAC), before and after commencing electrical stimulation (1 Hz). Values shown are mean and standard error for four neurons. Note that at less than one MAC, electrical stimulation resulted in prompt winddown after a brief windup such that by the third or fourth stimulus the minimum was reached, but more than MAC there was an initial strong activation followed by a slow winddown to reach the same minimum as occurred less than MAC. For the first 5 stimuli, the supra-MAC values were significantly different from the sub-MAC values (P < 0.05).
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Discussion
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The present results show that windup may be observed in lumbar spinal neurons at sub-MAC isoflurane concentrations, and that evoked responses are variably depressed at isoflurane concentrations larger than 1 MAC, especially during the first few stimuli. In some cases, the slope of the windup curve was reduced whereas in others the windup curve was shifted downward (Fig. 2). Simultaneously recorded hindlimb motor withdrawals also exhibit windup which was more uniformly depressed by isoflurane in a concentration-dependent manner (Fig. 3C). The importance of these findings for clinical anesthesia, as well as regarding isoflurane’s action at NMDA and other neurotransmitter receptors, are discussed.
A major finding of the present study is that isoflurane depressed windup of C fiber-evoked hindlimb withdrawals in a concentration-dependent manner. Isoflurane at supra-MAC concentrations also consistently reduced the responses of lumbar spinal neurons, particularly during the initial C fiber stimuli. Part of this depression probably reflects a generalized reduction in neuronal excitability, because the initial C fiber-evoked responses were reduced in a concentration-dependent manner, and in many cases the windup curve was shifted downward in a parallel manner with no reduction in slope of windup (Figs. 2C, 3A). One potential explanation for this effect is that windup is less evident at smaller anesthetic concentrations because of a "ceiling" effect, i.e., the neuronal response is maximal after the first 1–2 stimuli. At larger anesthetic concentrations, the initial responses are reduced but can still progressively increase across trials, implying that windup per se is not reduced. In other cases, the initial slope of windup was reduced by isoflurane (Fig. 2B) similar to its effect on withdrawals. Isoflurane uniformly depressed the motor response but had variable effects on neuronal windup. At least three scenarios might explain this discrepancy. One possibility is that the neurons found to be most sensitive to isoflurane were part of a neural pathway involved in the generation of nociceptive withdrawal reflexes, whereas the neurons less sensitive to isoflurane might be part of other pathways, e.g., spinothalamic. Another possibility is that mild depression of windup in each neuron along a nociceptive reflex pathway could summate to significant depression of motoneurons. A third possibility relates to the fact that, at 0.7 MAC, the mean motor response began to accelerate by the third stimulus (Fig. 3C), and the corresponding mean neuronal response (from Fig. 3A) had nearly reached its plateau, whereas at 1.1 and 1.4 MAC, the neuronal response never reached this plateau. This suggests that there might be a neuronal response threshold level that must be attained in order to initiate movement that results from repetitive C fiber stimulation.
A depressant action at the NMDA receptor is one mechanism by which isoflurane might reduce neuronal excitability and windup. Yamakura and Harris (8) reported that isoflurane depressed glutamate-evoked currents in oocytes expressing NMDA receptors. Ketamine, which acts like the noncompetitive NMDA antagonist MK-801, potentiated the depressant effects of isoflurane and other inhaled anesthetics at the NMDA receptor suggesting an additive or supra-additive interaction of these drugs at the NMDA receptor (11,12). Ketamine also dose-dependently reduced windup of a nociceptive reflex (13). Xenon and nitrous oxide are two other inhaled anesthetics that appear to have depressant effects almost exclusively on NMDA receptors (14,15) and it would be interesting to determine if they also depress windup. Other neurotransmitter/neuromodulator systems, particularly the neurokinin-1 (NK-1) receptor and its ligand, substance P, have also been implicated in windup (2,16) Indeed, windup is absent in mice lacking NK-1 receptors (17). However, NK-1 receptor antagonists decrease isoflurane MAC, but only minimally (approximately 10%–15%) (18) compared with the >80% reduction in MAC produced by NMDA receptor antagonists (19), suggesting that that the NMDA receptor might be more important than the NK-1 receptor for the immobilizing effect of inhaled anesthetics. Alternatively, isoflurane and other inhaled anesthetics might indirectly affect the NMDA receptor, for example, by inhibiting Na+ channels to depress presynaptic glutamate release (20) or by increasing 
-aminobutyric acid- or glycine-mediated inhibition. Opioids depress windup but, at intermediate doses, opioids preferentially depress the responses of the initial, but not latter, stimuli, similar to what was observed in the present study (21,22). How these varied actions ultimately sum to produce immobility has yet to be elucidated. The exact site within the glutamate receptor where this might occur is unknown, and anesthetics differ as to their propensity to affect the NMDA receptor (23).
In our previous study, we found that isoflurane did not depress dorsal horn neuronal responses to noxious thermal stimulation (10). The discrepancy between the present results and our prior study might be attributed to differences in the stimulation paradigm, e.g., 1-Hz electrical stimuli that caused windup versus a tonic nonsensitizing thermal stimulus. An electrical stimulus would be expected to activate all fiber types, whereas a thermal stimulus would activate primarily C fibers. In the present study, we only quantified C fiber responses. In addition, the mean neuronal depths differed between the two studies, as the neurons in the present study were deeper, with some at depths corresponding to lamina VII. Finally, many of the neurons presently studied were NS type, as compared with WDR neurons in the prior study (10). Any or all of these factors might explain the differing results.
The present experimental data showing effects of isoflurane on neuronal excitability and windup might have clinical significance. Whether a patient moves or not during surgery depends on many factors, including the intensity, frequency, and site of noxious stimulation and the anesthetic level. Thus, a submaximal noxious stimulus, if applied repeatedly, might not evoke movement if the anesthetic, even at a sub-MAC level, is able to depress windup within the spinal cord.
In the present study, we observed units exhibiting winddown, a phenomenon reported previously but of uncertain significance (24,25). That the C fiber-evoked responses were reduced to below spontaneous firing levels suggests that winddown may reflect a C fiber-evoked inhibitory action on these units, which is reduced (i.e., disinhibition) at larger (supra-MAC) concentrations. Such a response pattern might be explained if the neuron received inhibitory synaptic input from a presynaptic neuron exhibiting windup.
In summary, we found that isoflurane, at concentrations approximating MAC, depressed windup of motor withdrawals, with variable effects on lumbar spinal cord neurons, evoked by peripheral electrical C fiber stimulation. These data are consistent with our prior study of isoflurane’s effects on temporal summation (7).
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Acknowledgments
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Supported in part by NIH GM61283, GM57970 (to JFA), NSRA (to SLJ), 1PO1GM47818-10 (to RCD and EIE), Bethesda, MD, and the Center for Neural Communication Technology at the University of Michigan, Ann Arbor, MI via NIH 8P41EB002030-10, Bethesda, MD (http://www.engin.umich.edu/facility/cnct/).
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Footnotes
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Dr. Eger is a paid consultant to Baxter Healthcare Corp.
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Accepted for publication May 25, 2004.
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Top
Abstract
Introduction
