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Isoflurane, but Not Halothane, Depresses C-Fos Expression in Rat Spinal Cord at Concentrations that Suppress Reflex Movement After Supramaximal Noxious Stimulation

Jinks, Steven L., PhD*,; Antognini, Joseph F., MD*†,; Martin, John T., MD*,; Jung, S.-W., MD‡,; Carstens, Earl, PhD†, and; Atherley, Richard, BS*

doi: 10.1097/00000539-200212000-00028
ANESTHETIC PHARMACOLOGY: Research Report
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We investigated the effects of isoflurane and halothane on the induction of fos-like immunoreactivity (FLI) in the rat lumbosacral spinal cord after supramaximal noxious mechanical stimulation of the hindpaw. Compared with unstimulated controls (0.9% isoflurane), noxious stimulation at 0.9%–1.5% elicited significant (0.9%–1.5% isoflurane) increases in FLI bilaterally. FLI was distributed mainly in the superficial dorsal horn (laminae I–III) and, to a lesser extent, in the deep dorsal horn (laminae IV–VI) and intermediate zone (lamina VII), with three- to fivefold greater labeling ipsilaterally. At 1.8% isoflurane, mean FLI counts in all laminar regions were significantly smaller (1.7 ± 1.3 per section) compared with the other concentrations (11.4 ± 9.5, 7.5 ± 6.8, and 9.7 ± 6.6 at 0.9%, 1.2%, and 1.5%, respectively) but were not different from unstimulated controls. At sacral levels, we observed a bilateral distribution of FLI primarily in superficial laminae in unstimulated controls that was not significantly different at any isoflurane concentration. FLI counts were not significantly different across groups receiving halothane (0.9%–1.5%). FLI was reduced only at isoflurane concentrations that depressed both gross, purposeful movement and reflex withdrawal, whereas halothane did not cause depression even at concentrations that depressed withdrawal reflexes. Isoflurane and halothane may have differing effects on neuronal function and responses to noxious stimulation.

*Department of Anesthesiology and Pain Medicine and †Section of Neurobiology, Physiology and Behavior, University of California, Davis; and ‡Department of Anesthesiology, Keimyung University, Daegu, Korea

Supported in part by National Institutes of Heath Grants GM57970 and GM61283.

August 14, 2002.

Address correspondence and reprint requests to Joseph F. Antognini, MD, Department of Anesthesiology, TB-170, University of California-Davis, Davis, CA 95616. Address e-mail to jfantognini@ucdavis.edu.

The spinal cord is an important site of anesthetic action (1,2), but it is unclear at what sites anesthetics act to reduce gross, purposeful movement in response to a supramaximal stimulus. Some anesthetics may directly inhibit motoneurons (3,4). Many anesthetics also depress the nociceptive responses of dorsal horn neurons (5–10), resulting in a reduced afferent input to neural circuits generating movement. A drawback of these latter studies is the limitation of assessing anesthetic effects on one or a few neurons at a time. In recent years, immunohistochemical methods have been used to investigate the stimulus-dependent expression of the proteins of immediate early genes, such as c-fos, in populations of neurons (see reviews, Refs. 11–13). The few studies using this method to investigate anesthetics have all used intradermal hindpaw injection of formalin as a noxious stimulus and have reported variable effects of different anesthetics (14–17). Intradermal formalin elicits behavioral signs of persistent inflammatory pain but should not be considered to be equivalent to a supramaximal stimulus, such as a mechanical clamp, which is traditionally used to assess anesthesia in studies of minimum alveolar anesthetic concentration (MAC). Furthermore, although it is used widely in models of tonic nociception, formalin injection may not be a clinically relevant stimulus for studies of anesthetic-induced immobility. In this study, we investigated the effects of two volatile anesthetics, isoflurane and halothane, on the expression of fos-like immunoreactivity (FLI) elicited by a supramaximal mechanical clamp stimulus. We hypothesized that both isoflurane and halothane would decrease stimulus-evoked FLI in the spinal cord.

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Methods

The animal care and use committee at the University of California-Davis approved this study. Adult male Sprague-Dawley rats were either gently placed in an airtight chamber and anesthesia was induced by delivering isoflurane or halothane or, in most instances, were anesthetized in their plastic housing container before handling. The animals were removed and anesthesia was maintained by mask. Inspired gas was sampled from the mask by using a calibrated anesthetic analyzer (Rascal II; Ohmeda). The inspired anesthetic concentration was stabilized for 30–40 min at 0.8%–0.9%, 1.2%, 1.5%–1.6%, or 1.8% in animals anesthetized with isoflurane (n = 8–9 per group) and 0.8%–0.95% (average, 0.9%), 1.1%, 1.3%, or 1.5% in animals anesthetized with halothane (n = 4–6 per group). The upper concentration limits were estimated to be MAC equivalents when correcting for the inspired-alveolar gradient difference between halothane and isoflurane (18). Before noxious stimulation, each rat received only one anesthetic concentration. After the equilibration period, a noxious mechanical clamp was applied to the left hindpaw for 1 min and then removed. This A-clamp provides supramaximal noxious stimulation (9,19). The presence or absence of gross, purposeful movement and reflex withdrawal was noted. In a control group (n = 5), we maintained isoflurane at 0.8%–0.9% but did not apply the noxious stimulus. In all animals, the inspired anesthetic was then adjusted to 1.4% in animals anesthetized with isoflurane and 1.2% in animals anesthetized with halothane until they were killed.

In three additional rats, we performed a tracheostomy and jugular cannulation, after which rats were administered pancuronium (0.3 mg/kg IV) and ventilated with a rodent ventilator. Isoflurane was adjusted to 0.9%, and 30 min later the clamp was applied for 1 min, after which isoflurane was increased to 1.4% for 2 h. Because movements were prevented in these animals, they served as a control for animals that received an isoflurane concentration insufficient to prevent gross, purposeful movement.

In the initial studies, rectal temperature was periodically measured, whereas in later experiments, body temperature was monitored at the tympanic membrane. This was done because we noted a bilateral distribution of FLI in the sacral spinal cord and wanted to eliminate the possibility that it was elicited by the rectal probe. Body temperature in all animals was maintained at ≈37°C via a heating lamp and pad.

Two hours after application of the noxious stimulus, a thoracotomy was performed, and animals were perfused through the aorta with phosphate-buffered saline (250 mL) followed by 4% paraformaldehyde (500 mL). The lumbosacral spinal cord was removed, postfixed for 8 h, and then transferred to a 30% sucrose solution. Two to 3 days later, the cords were cut in 50-μm frozen sections and collected in 3 separate 24-well containers (Costar, Corning, NY) containing phosphate-buffered saline. One container was then processed immunohistochemically (i.e., sections were sampled at 150-μm intervals). Sections were first washed and blocked in 3% normal goat serum, followed by incubation in primary c-fos antibody (1:50,000; Arnel) for 24–36 h. The sections were then washed and exposed to secondary biotinylated (goat anti-rabbit) antibody, followed by an avidin-biotin-peroxidase complex reaction enhanced with biotinyl tyramide/H2O2. To visualize the reaction product, sections were subjected to a nickel-enhanced diaminobenzidine reaction. Finally, processed sections were mounted on microscope slides, coverslipped, and examined under the light microscope (Nikon E-400; Nikon, Melville, NY) for cell nuclei displaying black FLI. Counts of nuclei containing FLI were made in all sections at the L3 to S4 segments in each of the following regions bilaterally: lamina I, laminae II and III, laminae IV–VI, and in the intermediate and ventral horn (laminae VII–X). The number of midlumbar (≈L5) sections examined per animal was 24 ± 7. Counts of FLI were made manually by one of the investigators, who was blinded as to the anesthetic condition. Photomicrographs of selected sections were made with a video camera (DC-330; Dage-MTI, Michigan City, IN) and Scion Image (Scion Corp., Frederick, MD) software. To plot distributions, the five sections from each animal with the highest FLI counts were imaged and superimposed on a composite section of the L5 spinal cord taken from the atlas of Paxinos and Watson (20), and all sites of FLI were plotted as dots on the composite.

For each laminar location, the total FLI counts for all midlumbar sections per animal or FLI counts from the five sections per animal with the highest FLI counts were averaged for each anesthetic treatment group to determine mean FLI counts per section. We quantified FLI expression in ventral laminae because some animals moved with application of the clamp. Analysis of variance followed by post hoc testing (Tukey or Dunnett) was used to compare the effect of anesthesia on laminar distribution and cell count by using SPSS software (SPSS Inc., Chicago, IL). Anesthetic requirements were determined by using logistic regression of inspired anesthetic concentration and presence or absence of gross purposeful movement during application of the clamp. A P value <0.05 was considered significant. Data are expressed as mean ± sd.

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Results

Inspired isoflurane and halothane requirements to block gross, purposeful movement were 1.46% ± 0.33% and 1.12% ± 0.02%, respectively. Supramaximal noxious stimulation elicited a significant increase in FLI, particularly in superficial dorsal horn laminae I–III, but also, to a lesser extent, in the deeper dorsal horn (laminae IV–VI) and the intermediate zone (la- mina VII). Figure 1 A shows an example of the distribution of FLI in a stimulated animal at 0.9% isoflurane. The dashed white line indicates approximate laminar borders. Note the dense FLI in laminae I and II, as well as the group of labeled nuclei in the intermediate zone lateral to the central canal (arrow in Fig. 1 A). The distribution of evoked FLI was similar at intermediate concentrations of isoflurane (1.2% and 1.5%), as shown in Figure 1, B and C, whereas there was very little FLI at the largest (1.8%) isoflurane concentration (Fig. 1 D) or in the unstimulated control animals (0.8% isoflurane;Fig. 1 E).

Figure 1

Figure 1

Mean FLI counts are graphed as a function of isoflurane concentration for each laminar area in the ipsilateral (Fig. 2 A) and contralateral (Fig. 2 B) lumbar cord. FLI counts were generally three- to fivefold larger on the ipsilateral compared with the contralateral side. Analysis of variance revealed a significant effect of anesthetic concentration, with ipsilateral FLI counts in the 0.9%, 1.2%, and 1.5% isoflurane concentration groups being significantly different from the unstimulated control and the 1.8% isoflurane groups. FLI counts in the 0.9%, 1.2%, and 1.5% isoflurane groups did not differ significantly from one another, nor was there a significant difference between the unstimulated control and 1.8% isoflurane groups.

Figure 2

Figure 2

Mean FLI counts per section were 20 ± 17, 12.5 ± 9.2, 15.6 ± 7.1, and 4.2 ± 2.6, respectively, at 0.9%, 1.2%, 1.5%, and 1.8% isoflurane. There were no significant changes in FLI counts or laminar distribution among the 0.9%, 1.2%, and 1.5% isoflurane groups, and only at 1.8% isoflurane was there a significant decrease (by approximately 79%) in the mean FLI count (P < 0.05 compared with the 0.9%–1.5% groups). The results shown in Figure 2 for all midlumbar sections are borne out in the analysis of the five sections per animal with the largest FLI counts (composite plots in Fig. 3).

Figure 3

Figure 3

Isoflurane-anesthetized animals (n = 5) that did not display gross, purposeful movement (as would be sought in a MAC study), but that did exhibit reflex withdrawal responses, had greater FLI expression (total cell count per section, 10.6 ± 7.4) compared with animals (n = 9) that did not exhibit reflex withdrawal responses (3.0 ± 2.7;P < 0.05). The latter group received isoflurane at 1.75% ± 0.1%, whereas the former group was at 1.5% ± 0.2%.

Animals anesthetized at 0.9% isoflurane (n = 3) that received pancuronium had similar amounts of FLI as compared with nonparalyzed animals at the same isoflurane concentration (12.4 ± 6.2 compared with 11.4 ± 9.5 FLI counts per section). Ipsilateral and contralateral FLI expression in laminae VII–X was 1.9 ± 1.2 and 0.5 ± 0.3 FLI counts per section, respectively, in animals receiving pancuronium (n = 3), similar to the values obtained in animals that had not received pancuronium (1.5 ± 1.8 and 0.8 ± 1.0 FLI counts per section).

We also observed substantial FLI predominantly in the superficial dorsal horn of sacral sections bilaterally. Figure 4, A and B, shows examples from an unstimulated control animal and an animal receiving 1.8% isoflurane, respectively. There were no significant differences in FLI counts across anesthetic concentrations. The total FLI counts per section were 10.9 ± 8.4, 20.8 ± 11.9, 11.4 ± 3.9, and 11.7 ± 6.9 at 0.9%, 1.2%, 1.5%, and 1.8% isoflurane, respectively. Unlike the expression in the midlumbar region, FLI in the sacral sections was more equally distributed on both sides. For example, the ipsilateral and contralateral expression at 0.9% was 6.3 ± 4.5 and 4.6 ± 3.9 FLI counts per section, whereas at 1.2% it was 11.4 ± 6.1 and 9.5 ± 5.8 FLI counts per section, respectively. The animals that received no stimulation and no rectal probe (isoflurane 0.9%) had similar amounts of FLI in the sacral region (11.4 ± 8.5 FLI counts per section). The site of temperature measurement did not affect sacral FLI. In isoflurane-anesthetized animals, when rectal temperature was measured, the mean FLI count per section (total) was 14.3 ± 9.9, whereas in isoflurane-anesthetized animals, when ear temperature was measured, it was 11.8 ± 7.5.

Figure 4

Figure 4

In stimulated halothane-anesthetized animals, there were no significant differences in lumbar FLI counts across halothane concentrations; the unstimulated control rats had significantly less FLI expression in ipsilateral laminae II and III when compared with the 0.9%, 1.1%, 1.3%, and 1.5% groups. Figure 2, C and D shows mean FLI counts by laminar location in the ipsilateral and contralateral cord, respectively. At the largest halothane concentrations (1.3%–1.5%), no animal exhibited gross, purposeful movement, and only one animal had a weak simple withdrawal reflex, yet these groups exhibited substantial FLI expression. No lamina was preferentially affected by halothane, and analysis of the five sections exhibiting the largest counts of FLI from each animal revealed no dose-dependent anesthetic effects.

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Discussion

In this study, supramaximal mechanical hindpaw stimulation elicited a distribution of FLI in the lumbar enlargement, predominantly in superficial laminae and, to a lesser extent, in the deeper dorsal horn and intermediate zone, as well as contralaterally. The topography and laminar distribution are consistent with those observed in previous studies using noxious mechanical stimulation of the hindpaw (21–23). Our main finding was that FLI elicited by a supramaximal noxious mechanical stimulus was not affected in a concentration-dependent manner over the 0.9%–1.5% isoflurane concentration range, but it was significantly attenuated at the largest (1.8%) concentration. Likewise, there were no significant concentration-dependent effects of halothane on evoked FLI over the 0.9%–1.5% range. The data are discussed in relation to prior functional studies of volatile anesthetic effects on spinal sensorimotor processing.

Although the largest concentration of isoflurane (1.8%) significantly reduced FLI, there were no significant differences in the level of FLI across isoflurane concentrations in the peri-MAC range, i.e., the concentrations that just permit and just prevent gross, purposeful movement. This result is consistent with a previous electrophysiological study showing that isoflurane in the 0.9–1.1 MAC range had a minor depressant effect (approximately 15%) on the responses of rat lumbar dorsal horn neurons to noxious thermal stimulation (9). Moreover, in a recent electrophysiological study from our laboratory (24), isoflurane in the 0.75–1.4 MAC range was found to not significantly affect the responses of rat lumbar dorsal horn neurons to noxious thermal stimuli, even though movements were blocked above 1 MAC and spontaneous neuronal activity was reduced in a concentration-related manner. Any subtotal depressant effect that isoflurane might exert on nociceptive dorsal horn neurons may occur within a low range (<0.8%). This is supported by data from our previous study with goats (10), in which isoflurane was shown to depress responses of dorsal horn neurons to supramaximal noxious mechanical stimulation over the 0.3%–0.8% range, but not over the 0.8%–1.3% range, in which noxious-evoked movement ceases. Effects at these small concentrations, however, are not primarily responsible for the immobilizing effect that occurs at 1 MAC. It is interesting to note that isoflurane affected FLI only at the largest concentration studied (1.8%), which is also the concentration that prevented even simple reflex withdrawal responses. These withdrawal reflexes would normally not be considered “gross and purposeful” and hence would be negative movements in a traditional MAC determination. Nonetheless, the presence of such reflexes means that local neural circuits are being activated and thus may have contributed to the FLI that we observed at isoflurane concentrations of 0.9%–1.5%. We speculate that in this peri-MAC concentration range, isoflurane suppresses gross, purposeful movement largely by an action on motoneurons or premotor interneurons in the ventral horn. At larger concentrations, isoflurane further depresses dorsal horn sensorimotor processing associated with withdrawal reflexes.

That FLI was observed in the ventral laminae and contralateral spinal cord at sub-MAC isoflurane concentrations suggested the possibility that it was movement related. The three animals in which movement was abolished by the paralytic drug pancuronium exhibited a distribution of FLI that was indistinguishable from that observed in the animals that moved. In addition, animals that exhibited unilateral reflexive withdrawals, with no contralateral movement, also displayed FLI in the contralateral spinal cord. These results indicate that the observed bilateral distribution of FLI is independent of movement. Contralateral activation of spinal neurons might be explained by commissural projections of primary afferents or second-order neurons and is consistent with the bilateral receptive fields observed for some spinoreticular and medial spinothalamic tract projection neurons (25,26).

A potential, but unlikely, confounding factor is the effect of isoflurane and halothane on the transcriptional and translational processes that result in c-fos expression, unrelated to any anesthetic or analgesic effect. For this reason, in this study, animals received a single isoflurane or halothane concentration after the noxious stimulus was removed. We believe, however, that any effect, if present, was likely to be small. Hagihira et al. (15) found that halothane’s effect on FLI was present only in deeper laminae. Had halothane had an effect on c-fos expression unrelated to noxious stimulation (e.g., transcription or translation), then all laminae should have been affected. Furthermore, Hamaya et al. (27) reported that isoflurane had no depressant effect on c-fos messenger RNA expression in brain, suggesting that isoflurane does not alter the transcription of the c-fos gene. Suppression of FLI per se is not relevant from an anesthetic mechanisms perspective, because anesthetics act within seconds, whereas c-fos expression takes many minutes. Last, application of the noxious mechanical stimulus, although brief, likely led to an inflammatory process. However, the use of one isoflurane or one halothane concentration poststimulus would have eliminated any anesthetic-dose effect on inflammation-induced FLI.

The bilateral FLI observed mainly in superficial laminae at sacral segments is enigmatic. Similar counts of sacral FLI were obtained in both unstimulated control animals and in stimulated animals at all concentrations of isoflurane. The observed FLI cannot be attributed to inadvertent stimulation via the rectal temperature probe, because a similar distribution was observed after this procedure was discontinued, nor can it be attributed to handling of the animals’ tails, because they were gently handled and otherwise untouched before the induction of anesthesia. We can only speculate that the basal level of sacral FLI is related to physiological processes unrelated to nociception, such as thermoregulatory vasomotor control of the tail or descending (e.g., vestibulospinal) control of tail posture, functions that are apparently not influenced by isoflurane.

Our results, which show no significant effect of 0.9%–1.5% halothane on FLI, are consistent with a previous c-fos immunohistochemical study showing that 2% halothane (and 75% N2O) did not reduce spinal FLI induced by intradermal formalin in the rat hindpaw (14). They are also partly consistent with the study of Hagihira et al. (15), who reported that halothane at 0.5% and 1.5% did not significantly affect formalin-evoked FLI in lumbar dorsal horn laminae I–IV, although it decreased FLI in laminae V–X in a concentration-related manner. Fukada et al. (16) reported that halothane at 1 or 1.5 MAC depressed formalin-evoked FLI in animals in whom formalin-related behavioral responses were abolished, but not in animals that exhibited nocifensive responses. In this study, however, we observed no diminution in FLI even in animals whose withdrawal reflexes were abolished by halothane. Moreover, there is a discrepancy between these results, which show an absence of halothane effects on evoked FLI, and a body of electrophysiological data showing that halothane depresses spinal dorsal horn neuronal responses to noxious stimulation in a concentration-dependent manner (5–7). We have recently found that halothane at 0.75–1.4 MAC depressed the responses of rat lumbar dorsal horn neurons and concomitant withdrawal reflexes, evoked by noxious skin heating in a concentration-dependent manner (24). Much of the neuronal depression by halothane occurred between 0.9 and 1.1 MAC (24). Isoflurane’s effect on motor responses presumably occurred at ventral sites. It is presently difficult to reconcile the discrepancy between the c-fos and electrophysiological data (24), except to speculate that peri-MAC halothane concentrations more readily suppress synaptically evoked action potentials in dorsal horn neurons, whereas larger halothane concentrations (beyond those required clinically) are needed to block the signal transduction pathways involved in immediate early gene expression.

The authors acknowledge the technical assistance of Mirela Iodi Carstens.

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