Anesth Analg 2006;103:1453-1458
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000247732.33602.f5
ANESTHETIC PHARMACOLOGY
Isoflurane and Propofol Have Similar Effects on Spinal Neuronal Windup at Concentrations that Block Movement
Kevin P. Ng, MD, and
Joseph F. Antognini, MD
From the Department of Anesthesiology and Pain Medicine, University of California, Davis, California.
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Abstract
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BACKGROUND: We investigated the actions of isoflurane and propofol on neuronal windup in the spinal cord of intact rats. We hypothesized that propofol would depress windup more than isoflurane.
METHODS: In a cross-over design, rats received 0.8 and 1.2 minimum alveolar concentration (MAC) isoflurane and 0.8 and 1.2 ED50 (effective dose50%) of propofol, as recordings were made from single units in the lumbar cord (n = 13). Electrical stimuli were applied (20 stimuli at 0.1, 1, and 3 Hz). Neuronal responses were analyzed for those occurring in the C-fiber range (100–400 ms after each stimulus), combined C-fiber and afterdischarge range (100–1000 ms) and the 100–333 ms range for the 3 Hz stimuli. Absolute windup was also calculated (the sum of action potentials for 20 stimuli – 20 x response to the first stimulus).
RESULTS: At 1 Hz, total action potentials (mean, standard error) summed across the 20 stimuli (100–1000 ms range) were 571 ± 106 and 742 ± 214 for isoflurane (at 0.8 and 1.2 MAC) and 586 ± 148 and 641 ± 143 for propofol (at 0.8 and 1.2 ED50), respectively (P = NS); corresponding values for the 0.1 Hz stimuli were 345 ± 104, 370 ± 108, 430 ± 86, and 403 ± 106 (P = NS), and for the 3 Hz stimuli (100–333 ms range) were 266 ± 66, 333 ± 76, 343 ± 85, and 252 ± 72 (P = NS). Absolute windup in the 100–1000 ms range was greater for 1.2 MAC isoflurane at 1 Hz (445 ± 82, P < 0.01), when compared with absolute windup at 0.8 MAC isoflurane and 0.8 and 1.2 ED50 propofol (232 ± 31, 88 ± 65, and 210 ± 41, respectively).
CONCLUSIONS: These data suggest that isoflurane and propofol have similar effects on neuronal windup in the spinal cord, although there was enhanced absolute windup at 1.2 MAC isoflurane for the 1 Hz stimulus.
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Introduction
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Isoflurane and propofol are commonly used anesthetics during a variety of procedures, including abdominal, orthopedic, head, and spine surgeries. In addition, propofol is often used in the intensive care unit to aid management of critically ill patients. The mechanisms by which isoflurane and propofol produce anesthesia, however, are unclear. In particular, isoflurane and propofol blunt nociceptive responses to noxious stimuli. Propofol acts primarily at 
-aminobutyric acid, type A (GABAA) receptors (1), whereas isoflurane has actions at various receptor systems, including GABAA, N-methyl-d-aspartate (NMDA), and acetylcholine receptors (2,3). Thus, while propofol appears to act primarily at one receptor, isoflurane acts at many receptors, although isoflurane’s effect on each of these receptors varies (3) and it is unclear which of these actions is important.
In this study we compared the effects of isoflurane and propofol on spinal nociceptive responses to repetitive noxious stimulation. This paradigm produces neuronal windup, whereby the firing of neuronal action potentials increases in response to each successive stimulus. Neuronal windup is dependent, in part, on the NMDA receptor, as antagonism of the NMDA receptor depresses or abolishes windup (4,5). Matute et al. (6) reported that sevoflurane, a volatile anesthetic with NMDA receptor actions similar to isoflurane (7), caused more depression of neuronal windup than propofol in an in vitro preparation using spinal cord slices. This effect could be due to NMDA receptor depression caused by volatile anesthetics. We have found, however, that isoflurane has no depressive effect on spinal neuronal windup in the concentration range that abolishes movement in response to a supramaximal noxious stimulus (8), a result different from that of Matute et al. (6). Thus, we hypothesized that, in the peri-MAC (minimum alveolar concentration) range, windup would be more depressed during propofol anesthesia, as compared to isoflurane anesthesia.
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METHODS
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The local (University of California, Davis) animal care and use committee approved this study. Adult male rats (Sprague-Dawley, Charles River, Wilmington, MA) weighing 460–575 g were anesthetized with isoflurane (4%–5%) in a chamber. Anesthesia was maintained via mask (2%) and a tracheostomy (14-gauge catheter) placed via an anterior neck incision. The jugular vein and carotid artery were cannulated using PE-50 tubing for administration of fluids and drugs, and measurement of arterial blood pressure, respectively. A laminectomy was made to expose the spinal cord at the approximate L2-S2 spinal cord segment. The rat was placed in a stereotaxic frame using ear bars and two vertebral clamps. After the surgical procedures, pancuronium (0.2–0.4 mg/kg, every 1–2 h) was administered IV. Warm agar was poured over the exposed spinal cord to form a well which was then filled with saline. A tungsten electrode (10–12 
; FHC, Bowdoinham, ME) was inserted into the spinal cord at the approximate L5 segment using a hydraulic microdrive (Kopf Instruments, Tujunga, CA). Extracellular action potentials were amplified and filtered (300–3000 Hz) and recorded onto a computer using Chart5 software (ADInstruments, Colorado Springs, CO). The electrode was advanced in 2–5 µm steps while the ipsilateral hindpaw was palpated to find neurons that responded to light touch. We sought neurons that also responded to increasing stimulation, including noxious stimuli (pinching). These were classified as wide-dynamic range neurons. We studied only one neuron in each rat. Neuronal depth was estimated from the distance traveled by the microdrive, using the spinal cord surface as zero. Needle electrodes (platinum E-2, Astro-Med, West Warwick, RI) were placed into the receptive field on the hindpaw to determine that these neurons displayed windup, i.e., increased numbers of action potentials with repetitive stimulation at 1 Hz (9). The threshold for firing was determined by gradually increasing the applied voltage until action potentials in the C-fiber latency range (100–400 ms) were elicited at least 50% of the time (8). This voltage was taken as the C-fiber threshold.
We used a cross-over design to determine isoflurane’s and propofol’s effects on windup. In half of the rats, we maintained anesthesia with isoflurane, and after determination of windup, we switched to propofol, while in the other group, before determining windup responses, we immediately switched to propofol, determined windup, and then switched to isoflurane anesthesia. The anesthetic concentrations used were 0.8 and 1.2 MAC isoflurane and the propofol infusion rate was 0.8 and 1.2 x, which prevents movement in 50% of rats (i.e., the effective dose 50%, ED50). We assumed an isoflurane MAC = 1.2% and propofol ED50 = 600 µg · kg–1 · min–1 based on earlier studies in our laboratory (10,11). We waited at least 15 min between changes to new anesthetic levels (e.g., when switching from 0.8 MAC isoflurane to 1.2 MAC isoflurane) and at least 30–40 min when switching from isoflurane to propofol and vice versa. At each of these anesthetic levels, we determined windup responses to a train of 20 electrical stimuli applied to the receptive field via the needle electrodes. The stimuli were at 2–3 x C-fiber threshold (8), 0.5 ms duration, and applied at 0.1, 1, and 3 Hz. We waited 3–5 min between each train of stimuli. At the end of the experiment, animals were euthanized with additional anesthetic and IV potassium chloride.
Action potentials were counted after each stimulus in the 20-stimuli train. Action potentials in the 0–100 ms period were considered A-fiber responses, while those in the 100–400 ms range were considered C-fiber responses, and those in the 400–1000 ms range after each stimulus were afterdischarge. Because the 3 Hz stimuli occurred every 333 ms, we could not use the same data analysis method. Thus, for the 3 Hz stimuli, we counted the action potentials elicited in the 0–100 and 100–333 ms latency ranges.
We used an area under the curve (AUC) (8) analysis to determine windup: the action potentials over the 20 stimuli in each latency range (A-fiber, C-fiber, afterdischarge) were summed and compared across anesthetic conditions using one-way repeated measures analysis of variance, followed by post hoc testing (Student–Newman–Kuels). We also compared absolute windup (the sum of action potentials for 20 stimuli – 20 x response to the first stimulus) (8). A P < 0.05 was considered significant. Data are presented as mean and standard error.
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RESULTS
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Thirteen neurons were studied in 13 animals. The mean recording depth was 633 ± 96 µm. Figure 1 shows an individual example of a neuron in which windup was observed at 1 Hz. Note that the response was not substantially affected by changing the anesthetic condition.
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Figure 1. Shown are individual examples of action potential recordings from a single neuron in the lumbar spinal cord of a rat. The recordings were obtained at 0.8 and 1.2 minimum alveolar concentration (MAC) isoflurane (ISO) and at the propofol (PROP) effective dose that produces immobility 50% of the time (ED50). A repetitive electrical stimulus was applied 20 times (at 1 Hz) to the neuron’s receptive field on the hindpaw. Note that with each subsequent electrical stimulus the neuronal response increased. The responses did not differ among the anesthetic conditions. Note the large stimulus artifacts occurring every 1 s.
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Summary data for 0.1, 1, and 3 Hz are shown in Figure 2. Note that for 1 Hz, windup occurred over the course of the 20 stimuli for the C-fiber range (100–400 ms) and especially for the combined C-fiber and afterdischarge range (100–1000 ms). However, the transition from one concentration to another, or from one anesthetic to the other, did not markedly alter the windup response. In fact, there was a trend for the responses at 1.2 MAC isoflurane to be more than the responses at the other anesthetic conditions. Windup was observed in some animals at 0.1 Hz, but on average there was little windup at 0.1 Hz. Overall, no windup was observed at 3 Hz. However, absolute windup for the 1 Hz stimulus was greater at 1.2 MAC isoflurane when compared with other anesthetic conditions (Table 1).
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Figure 2. Summary data are shown for responses of 13 neurons (mean and standard error) evoked with 20 stimuli at 0.1, 1, and 3 Hz. For clarity, the error bars have been omitted from every other mean data point. In (A) the C-fiber responses and C-fiber + afterdischarge are shown for the 0.1 Hz stimuli. No significant windup occurred and there was no difference among the four anesthetic conditions: 0.8 and 1.2 MAC (minimum alveolar concentration for isoflurane, ISO) and 0.8 and 1.2 ED50 (effective dose, 50% effect for propofol, PROP). (B) Responses (C-fiber, C-fiber + afterdischarge) for the 1 Hz stimuli are shown. Windup occurred as demonstrated by the increasing response to each subsequent stimulus, although windup was minimal for propofol at 0.8 ED50. There was no significant difference among the four anesthetic conditions, however, there was a trend for the responses at 1.2 MAC isoflurane to be greater than those of the other anesthetic conditions. (C) C-fiber responses (in the 100–333 ms latency range) for the 3 Hz stimuli are shown. There was no significant difference among the four anesthetic conditions.
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At 1 Hz, the total number of action potentials summed across the 20 stimuli (for the C-fiber + afterdischarge range) were 571 ± 106 and 742 ± 214 for isoflurane (at 0.8 and 1.2 MAC) and 586 ± 148 and 641 ± 143 for propofol (at 0.8 and 1.2 ED50), respectively (P = NS); corresponding values for the 0.1 Hz stimuli were 345 ± 104 and 370 ± 108 for isoflurane (at 0.8 and 1.2 MAC) and 430 ± 86 and 403 ± 106 for propofol (at 0.8 and 1.2 ED50) (P = NS). At 3 Hz, the total number of action potentials summed across the 20 stimuli (100–333 ms range) were 266 ± 66, 333 ± 76 for isoflurane (at 0.8 and 1.2 MAC) and 343 ± 85 and 252 ± 72 for propofol (at 0.8 and 1.2 ED50), respectively (P = NS).
Windup was not observed in the A-fiber range (Fig. 3), however, A-fiber responses were slightly, but significantly, lower during propofol anesthesia than during isoflurane anesthesia. For the 0.1 Hz stimuli, the responses at 0.8 and 1.2 MAC isoflurane were greater than those during 0.8 and 1.2 ED50 propofol, whereas with the 1 Hz stimuli, the 1.2 MAC isoflurane A-fiber responses were greater than those at 0.8 and 1.2 ED50 propofol (Fig. 3).
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Figure 3. Summary data are shown for the A-fiber responses of 13 neurons (mean and standard error) evoked with 20 stimuli at 0.1, 1, and 3 Hz. For clarity, the error bars have been omitted from every other mean data point. The responses at 0.8 and 1.2 MAC (minimum alveolar concentration) isoflurane were slightly, but significantly, greater than the responses at 0.8 and 1.2 ED50 (effective dose, 50% effect) propofol for the 0.1 Hz stimuli (*P < 0.05), whereas with the 1 Hz stimuli, the response at 1.2 MAC isoflurane was greater than the responses at 0.8 and 1.2 ED50 propofol (*P < 0.05). At 3 Hz, the response at 1.2 MAC isoflurane was greater than the responses at 1.2 ED50 propofol (*P < 0.05).
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DISCUSSION
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The results of the present study indicate that isoflurane and propofol similarly affect windup of spinal neuronal responses to repetitive noxious electrical stimulation, although there was enhanced absolute windup at 1.2 MAC isoflurane for the 1 Hz stimulus. Our prior finding of minimal effect on windup, but enhanced absolute windup, in the transition from 0.8 to 1.2 MAC isoflurane (8) is consistent with the current data. We did not examine neuronal responses below 0.8 MAC isoflurane or 0.8 ED50 propofol. In a previous study, however, we examined spinal neuronal windup in decerebrate rats, using isoflurane concentrations between 0 and 1.2 MAC (12). We found that isoflurane depressed responses between 0 and 0.8 MAC, with no further depression between 0.8 and 1.2 MAC, this latter finding being similar to what we presently observed. Furthermore, other investigators have reported that anesthetics depress spinal neuronal responses to peripheral stimulation (13). Thus, it seems reasonable to speculate that isoflurane and propofol cause similar depression of spinal neuronal windup between 0 and 0.8 MAC (or ED50 for propofol). However, because we did not specifically study a control group that received no anesthetic, we cannot make any firm conclusions regarding what effect isoflurane and propofol would have had on neuronal windup in the 0–0.8 MAC-ED50 range. Finally, we did not study a large group of neurons; therefore we cannot exclude the possibility that we missed differences between propofol and isoflurane with respect to windup.
Isoflurane acts at various neurotransmitter receptor systems, including the GABAA, NMDA, and acetylcholine receptors (2,3). For example, by enhancing the effect of GABA at its receptor, isoflurane increases neuronal inhibition. Isoflurane also depresses the NMDA receptor, an action that would decrease excitatory neurotransmission. Propofol acts at both GABA receptors and glycine receptors, although the GABAA receptor appears to be the more important site of action. Jurd et al. (1) used mice with mutated GABAA receptors to probe propofol’s anesthetic actions. When the ß-3 subunit was mutated (asparagine 265 to methionine), the mice were profoundly resistant to propofol, as determined using the righting reflex and hindlimb withdrawal in response to pinching. Interestingly, these mice also had a modest resistance to halothane (approximate 20% increased MAC), suggesting that immobility produced by volatile anesthetics are only partly explained by actions at the GABAA receptor. The data from Jurd et al. (1) also indicate that, at least with respect to the righting reflex and nociception, propofol’s action at the glycine receptor is unimportant, otherwise the mutant mice would have displayed only a moderate resistance to propofol.
We used a windup paradigm that involves repetitive stimulation with an electrical current. The mechanisms underlying neuronal windup in the spinal cord likely involve the NMDA receptor and the neurokinin receptor (5,14). Administration of antagonists at these receptors decreases windup but, by themselves, antagonists do not necessarily abolish windup, suggesting that more than one receptor system is involved (5). Interestingly, we did not observe windup at 3 Hz. Windup peaks at stimulus frequencies approximately 1 Hz, and declines at frequencies >1–2 Hz, however, it would not be expected to be absent at 3 Hz (5). The decline in windup at higher frequencies could have been due to decreased conduction velocity (5) as well as heterotopic synaptic inhibition (15). It is possible that our paradigm produced sensitization, including receptive field expansion. Thus, the lack of windup with the 3 Hz stimuli might be secondary to an already maximal response with the first 1–2 stimuli of the train of 20. Also, the short interval between 3 Hz stimuli obscured action potentials in the long-latency range (400–1000 ms) and thus might have affected our interpretation of the 3 Hz data. Lastly, we did not test mechanical stimulation or use naturally occurring stimuli, so we do not know if our conclusions extend to those types of stimulation.
The role of the GABAA receptor in windup is unclear, although Reeve et al. (16) reported that bicuculline, a GABAA antagonist, enhanced spinal neuronal windup of C-fiber-evoked response. However, Seagrove et al. (17) reported that bicuculline did not affect the C-fiber-evoked response. Both of these groups reported that bicuculline significantly enhanced the A
-fiber response to electrical stimulation, suggesting a GABA component of the A-fiber response. In the present study we found that A-fiber responses were slightly lower during propofol anesthesia when compared with those during isoflurane anesthesia. Thus, propofol, because of its predominant GABAergic effect, might have suppressed the A-fiber response, when compared with isoflurane.
The similarity between propofol and isoflurane with respect to windup has several possible explanations. Windup of a neuron could be inhibited by enhancing GABAergic transmission (as might occur with propofol) or by decreasing glutamatergic excitatory transmission (as might occur with isoflurane), or both. Propofol and isoflurane may directly (at a spinal site) or indirectly (at a supraspinal site) depress a final common pathway, e.g., the nociceptive spinal neurons presently recorded. Lastly, perhaps isoflurane action at NMDA receptors is unimportant in the intact animal. Eger et al. (7,18,19) have recently shown that conventional anesthetics such as isoflurane do not appear to produce immobility by actions at the NMDA receptor. Repetitive electrical stimuli, especially at 1–10 Hz, are (or are nearly) supramaximal with respect to MAC, and yet neuronal windup is not consistently evoked, as demonstrated by our 3 Hz data. Furthermore, Eger et al. (19) have shown that administration of MK-801 similarly decreases etomidate and isoflurane requirements to produce immobility. These data indicate that an anesthetic that acts almost exclusively at the GABAA receptor (etomidate), and one that acts at a variety of receptors (isoflurane), are similarly affected by blockade of the NMDA receptor, suggesting that the NMDA receptor is not important to nociceptive responses with either anesthetic. This scenario is consistent with our finding that neuronal windup is similar between propofol- and isoflurane-anesthetized animals, insofar as propofol, like etomidate, acts almost exclusively at the GABAA receptor to produce immobility (1).
Isoflurane and propofol are widely used in the clinical setting and can be easily titrated in response to changes in stimulation in the operating room. Propofol has been used to facilitate management of critically ill patients who require mechanical ventilation. Our data indicate that when propofol and isoflurane are administered in equipotent doses, similar effects on nociceptive responses should occur. Interestingly, isoflurane and propofol do not seem to have significant analgesic properties at sedative doses (20–22), and only when anesthetic doses are used that produce unconsciousness does depression of nociception occur.
In summary, isoflurane and propofol had similar effects on neuronal windup in the spinal cord, although we did observe enhanced windup (in the combined C-fiber and afterdischarge range) at 1.2 MAC isoflurane for the 1 Hz stimulus. In conjunction with other data (7,18,19) the present results suggest that, insofar as neuronal windup is partly dependent on the NMDA receptor, anesthetic action at the NMDA receptor is not critically important to immobility produced by anesthesia.
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ACKNOWLEDGMENTS
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We thank Emigdio Bravo for his technical assistance.
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Footnotes
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Accepted for publication September 14, 2006.
Supported in part by National Institute of Health Grants GM61283, 47818, and 57970.
Address for correspondence and reprint requests to Joseph F. Antognini, MD, Department of Anesthesiology and Pain Medicine, TB-170, University of California, Davis, Davis, California 95616, 530-752-7809. Address e-mail to jfantognini{at}ucdavis.edu.
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Abstract
Introduction
