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The Differential Effects of Halothane and Isoflurane on Windup of Dorsal Horn Neurons Selected in Unanesthetized Decerebrated Rats

Mitsuyo, Toshihiko, MD, PhD*; Dutton, Robert C., MD; Antognini, Joseph F., MD‡§; Carstens, Earl, PhD§

doi: 10.1213/01.ane.0000230605.22930.52
Analgesia: Research Report

Halothane and isoflurane, in the peri-minimum alveolar anesthetic concentration (MAC) range, exert differential effects on spinal nociceptive neurons, whereby halothane further depresses their responses from 0.8 to 1.2 MAC, whereas isoflurane does not. We presently investigated if these anesthetics differentially affect windup, the progressive increase in neuronal responses to repetitive noxious stimuli, over a broad concentration range from 0 to 1.2 MAC. In decerebrated rats, single-unit recordings were made from dorsal horn neurons exhibiting windup to 20 1-Hz C-fiber strength electrical stimuli. Halothane and isoflurane (0, 0.4, 0.8, and 1.2 MAC) were tested in a counterbalanced crossover protocol. Increasing halothane and isoflurane from 0 to 1.2 MAC progressively suppressed the response to the first stimulus, as well as summed responses to all stimuli (to 34% ± 8% and 50% ± 8%, respectively; P < 0.05). Absolute windup (summed response minus 20× the first response) was suppressed by both anesthetics from 0 to 0.8 MAC, with further depression by halothane but not isoflurane at 1.2 MAC. Responses of neurons isolated at 0 MAC were partially, but never totally, depressed at 0.8 MAC. The dose-dependent suppression of windup is consistent with reduced temporal summation of pain. Further depression at 1.2 MAC halothane, but not isoflurane, suggests different sites of immobilizing action for these two anesthetics. Immobility seems to not be mediated by severe anesthetic depression of a subpopulation of nociceptive neurons.

IMPLICATIONS: Halothane and isoflurane dose-dependently inhibited dorsal horn neuronal windup in the 0–0.8 minimum alveolar anesthetic concentration (MAC) range, consistent with their ability to reduce temporal summation for pain. Halothane, but not isoflurane, further depressed windup at 1.2 MAC, suggesting different sites of immobilizing action for these anesthetics.

From the *Department of Anesthesiology and Resuscitology, Ehime University Medical School, Matsuyama, Japan; †Department of Anesthesia and Perioperative Care, University of California, San Francisco; and ‡Department of Anesthesiology and Pain Medicine and §Section of Neurobiology, Physiology, and Behavior, University of California, Davis.

Supported, in part, by NIH GM 57970, GM61283 and P01-GM47818.

Accepted for publication May 22, 2006.

Address correspondence and reprint requests to Earl Carstens, PhD, Section of Neurobiology, Physiology & Behavior, University of California, Davis, 1 Shields Ave., Davis, CA 95616. Address e-mail to

Depression of spinal nociceptive transmission may be an important mechanism by which anesthetics produce immobility. In the peri-minimum alveolar anesthetic concentration (MAC) range, halothane depresses neuronal responses to noxious stimulation in the spinal dorsal horn, whereas isoflurane generally does not (1–4), even though nociceptive reflexes are depressed by both anesthetics over this range. This suggests that halothane depression of nociceptive dorsal horn neurons contributes to immobility, whereas isoflurane presumably acts at more ventral sites in the spinal cord to produce immobility. Such an interpretation of differential action is limited however, because halothane and isoflurane’s action on neuronal responses over the 0–0.8 MAC range are incompletely known. Whereas halothane depresses dorsal horn spinal neurons in this lower range, there are limited similar data for isoflurane (5–7). For example, depression of dorsal horn neurons by either anesthetic at small (0–0.8 MAC) concentrations may provide a state of reduced sensorimotor transmission upon which further increases in anesthetic concentration (0.8–1.2 MAC) can effectively block noxious stimulus-evoked movement. In this context, it is important to understand the effects of these anesthetics on spinal nociceptive transmission over a broad concentration range.

In the present study, we investigated the effect of halothane and isoflurane on lumbar dorsal horn neuronal responses to noxious stimulation over a broad range of concentrations (0–1.2 MAC) that are not usually included in other studies. We recorded neuronal responses to repetitive C-fiber strength electrical stimulation, including windup, as a measure of nociceptive activity (2–4,8–13). Windup represents a potential mechanism underlying the influence of temporal summation on anesthetic requirements (14). We hypothesized that both isoflurane and halothane depress nociceptive responses in a concentration-dependent manner up to 0.8 MAC, whereas halothane, but not isoflurane, induces further depression from 0.8 to 1.2 MAC. A second aim of the study was to evaluate the sampling of nociceptive neurons. In most in vivo experiments, such neurons are sought under anesthetic conditions of 0.8–1 MAC. However, this strategy could potentially miss neurons that are already maximally depressed at anesthetic concentrations less than 0.8 MAC. We specifically addressed the hypothesis that depression of a subpopulation of such nociceptive neurons that are particularly sensitive to small anesthetic concentrations contributes to anesthetic-induced immobility. Hence, we investigated if any neurons selected during 0 MAC became completely unresponsive at larger anesthetic concentrations.

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Adult male Sprague-Dawley rats weighing 476 ± 64 g (mean ± sd) (Harlan, San Diego, CA) were used. The experimental procedures were approved by the University of California Davis Animal Use and Care Advisory Committee. Rats were housed one to two per cage with food and water ad libitum.

Rats were initially anesthetized with isoflurane 3%–4% delivered in a balance of oxygen at 1 L/min in a chamber and then moved to mask anesthesia (isoflurane 2%) during surgery. The animal’s lungs were ventilated via a tracheostomy tube with a positive-pressure pump (Harvard Apparatus, Holliston, MA) at a rate and tidal volume that maintained end-expiratory carbon dioxide between 30 and 40 mm Hg as monitored by a calibrated Ohmeda Rascal II gas analyzer (GE Healthscience, Madison, WI). A jugular vein was cannulated with PE-50 tubing for fluid delivery, a carotid artery was cannulated with a 22-gauge intravascular catheter (Quik Cath; Baxter Health Care, Deerfield, IL) for arterial blood pressure monitoring (PB240; Tyco PB, Pleasanton, CA), and a loose ligature was placed around the other carotid artery. A midline skin incision was made over the back from L6 to T11 spinous processes, and the lumbar spinal cord was exposed by laminectomy.

Precollicular decerebration (without spinalization) allowed studies during 0 MAC while preserving mid- and hindbrain pathways thought to modulate movement responses to noxious stimuli (15,16). A midline incision exposed the sagittal, coronal, and lambdoid sutures of the cranium. Burr holes were made laterally along the insertions of the temporalis muscles and anterior to the coronal and posterior to the lambdoid sutures, using a high-speed drill. After ligating the remaining carotid artery, the parietal and squamous portions of the temporal bones were removed. The posterior cerebral hemispheres were then gently aspirated under direct vision to expose the superior colliculi, a blade vertically inserted to produce a precollicular transection, and the remaining cerebral hemispheres and thalamus were removed by aspiration (15–17). Hemostasis was secured by applying thrombin solution-soaked cotton pledgets to the exposed surfaces of the brain. Saline or hetastarch (Hespan; Du Pont Merck, Wilmington, DE) were infused to replace blood loss, and isoflurane was titrated to maintain a targeted mean arterial blood pressure of 70–90 mm Hg. The rat was allowed to stabilize for at least 1 h after decerebration before recording. Core body temperature was maintained at 37°C ± 0.2°C with a lamp and heating pad. The animals were given pancuronium bromide (0.1–0.3 mg/h; Baxter, Deerfield, IL).

The animal was placed in a stereotaxic frame with vertebral clamps on T12 and L2 vertebral bodies. The dura was opened, and the exposed cord was covered with warm agar. A Teflon-coated tungsten microelectrode (8–11 MÓHgr; FHC, Bowdoinham, ME) was then advanced in the dorsal horn of the spinal cord by hydraulic microdrive (Kopf Instruments, Tujunga, CA) to record extracellular action potentials. These were amplified and displayed by conventional means and recorded (along with the electrocardiogram and arterial blood pressure) with a Powerlab interface and Chart software (AD Instruments, Grand Junction, CO) and stored for off-line spike discrimination and analysis.

Single units were searched at 0.0 MAC using innocuous mechanical stimulation of the plantar surface of the ipsilateral hindpaw. Only units that responded differentially to touch and pinch (i.e., wide-dynamic range neurons [WDR]) within the L4–6 dermatomes (18,19) were selected. They were further tested with electrical stimulation using a S48 stimulator (Grass-Telefactor; Astro-Med, West Warwick, RI) and stimulus isolation unit with constant current output (Grass model PS1U6) delivered by subcutaneous needle electrodes inserted within the receptive field area. Only units exhibiting a reproducible discharge at C-fiber latency (100–400 ms) (10) were investigated further. A 1-Hz stimulus train (20 pulses; 0.5-ms pulse duration) was delivered at an intensity of approximately 3 times the C-fiber threshold (4,12,13).

Windup responses were first recorded at 0.0 MAC. In a crossover design (4), isoflurane or halothane was then administered in counterbalanced order such that each anesthetic was tested first in one half of the experiments. Windup responses were recorded during either isoflurane 0.6% (0.4 MAC), 1.1% (0.8 MAC), and 1.7% (1.2 MAC) or halothane 0.4% (0.4 MAC), 0.7% (0.8 MAC), and 1.1% (1.2 MAC); the approximate MAC fractions were based on previous studies from our laboratory (1,20,21). After changing the anesthetic concentration, we allowed equilibration times of at least 15 and 20 min for isoflurane and halothane, respectively, based on their blood-gas solubility coefficients. The order of presentation of different halothane and isoflurane concentrations was counterbalanced across experiments. After completing one anesthetic series, anesthesia was discontinued, and only oxygen was administered to return to the 0 MAC level, followed by repetition of the windup paradigm. The other anesthetic was then introduced via its own separate vaporizer, and, after an equilibration period of 20–30 min, the windup paradigm repeated at 0.4, 0.8, and 1.2 MAC, as described above. Control responses were again determined at 0 MAC, and upon completion of the experiment, each animal was killed by overdose of pentobarbital IV.

Action potentials were identified and counted using off-line spike discrimination and analysis with the Chart software. Action potentials that occurred within a fixed time period (latency range) after each stimulus were counted; these latency ranges were 0–100 ms (A-fiber range), 100–400 ms (C-fiber range), 400–1000 ms (afterdischarge [AD], i.e., post–C-fiber response), and 100–1000 ms (C-fiber plus AD) after each stimulus. For each latency range, responses were summed (across all 20 stimuli); this value is referred to as area under the curve (AUC). Absolute windup was calculated as the AUC minus 20 times the initial response (i.e., number of action potentials evoked by the first stimulus in each train of 20), as previously described (8,9). Absolute windup provides a measure of increased firing above that elicited by the first stimulus in the train. For the AUC and absolute windup calculations, the evoked action potentials occurring during the C-fiber plus AD range (100–1000 ms) were combined (4). We also determined the slope of windup, calculated as the slope of the linear regression line of the action potential responses (100–1000 ms), to the first 10 stimuli. Spontaneous firing rates at each anesthetic concentration were measured by summing the total number of action potentials during the 3 s before the first electrical stimulus.

Single-factor analysis of variance with post hoc Scheffe testing (StatView; Abacus Concepts, Inc., Berkeley, CA) was used for overall comparisons of dose-response effects on initial response, AUC windup, absolute windup, slope of windup, and spontaneous firing rate. Two-factor analysis of variance was used for overall comparisons of the differences between actions of halothane and isoflurane. A paired t-test was used to compare results during the steps from 0.8 to 1.2 MAC. Arterial blood pressure values were not normally distributed and were compared across anesthetic concentrations by the Mann-Whitney U-test. Data are mean ± se of the mean (sem).

Each neuron included in the dose-response studies was classified as having a windup, flat, or wind-down response according to the slopes values >1.0, 1.0 to −1.0, and <−1.0 action potentials-stimulus, respectively, for the averaged slope values during 0.0 MAC of that neuron. Neurons were included for analysis only if mean arterial blood pressure values were ≥50 mm Hg throughout the dose-response tests (22).

A delayed onset of windup was defined as the absence of response to the first 2 or more electrical stimuli in the train, with subsequent stimuli evoking responses having a slope >1.0 spike per stimulus over the next 10 stimuli.

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Thirty-three units (1 unit/rat) were tested with different concentrations of halothane and isoflurane, including 18 units exhibiting windup (Fig. 1), 13 with flat responses, and 2 exhibiting wind-down. All tested units were of the WDR type. An additional 66 units with flat responses were recorded at 0 MAC but were not tested with anesthetics. Units were located at a mean depth of 553 ± 29 μm (range, 344–837 μm), which corresponds to mid- to deeper laminae of the dorsal horn.

Figure 1.

Figure 1.

Complete dose-response data for both halothane and isoflurane were obtained in 12 units, and partial data in an additional 6 units. The left columns in Figure 1 (A and B) show individual examples of the progressive increase in response at 0 MAC. Increasing the concentration of both anesthetics progressively reduced windup (Fig. 1, A and B; right-hand columns). Figure 2 plots averaged responses for halothane (Fig. 2A–D; n = 12) and isoflurane groups (Fig. 2E–H; n = 12). Figure 2 separately shows data for A-fiber (Fig. 2, A and E), C-fiber (Fig. 2, B and F), AD (Fig. 2, C and G), and total C-fiber plus AD ranges (Fig. 2, D and H). A-fiber responses did not exhibit windup, and both the initial response and AUC windup were significantly depressed in a concentration-dependent manner by halothane (Fig. 2A; P < 0.05 and P < 0.01, respectively) although not by isoflurane (Fig. 2E). The mean C-fiber (Fig. 2, B and F), AD (Fig. 2, C and G), and C-fiber + AD responses (Fig. 2, D and H) all exhibited concentration-dependent reductions in AUC windup (P < 0.05 in all cases) as manifested by a downward shift and reduced slope of windup curves, with the exception that there was no further change in the step from 0.8 to 1.2 MAC isoflurane (Fig. 2F–H; O versus ▴). In addition, the initial response was depressed by both anesthetics in a dose-dependent manner, except in the step from 0.8 to 1.2 MAC isoflurane (Fig. 2F–H).

Figure 2.

Figure 2.

Because anesthetic effects were qualitatively similar for C-fiber and AD responses, statistical analyses were performed on the combined (C-fiber + AD; 100- to 1000-ms latency) response (Fig. 2, D and H). At 0 MAC (Fig. 2, D and H; open triangles), the slopes of the halothane and isoflurane windup groups were not significantly different (2.03 ± 1.40 versus 2.21 ± 1.39 action potentials-stimulus, respectively) and did not change significantly upon retesting at 0 MAC after completion of the initial anesthetic series. Figure 3A plots mean initial responses versus anesthetic concentration to illustrate significant concentration effects for both anesthetics (P < 0.01 and 0.05 for halothane and isoflurane, respectively) with no significant difference between anesthetics.

Figure 3.

Figure 3.

AUC windup was dose-dependently suppressed by halothane and isoflurane (to 34% ± 8% and 50% ± 8%, respectively, at 1.2 MAC; P < 0.01 for both) with no significant difference between anesthetics (Fig. 3B). In contrast, absolute windup was significantly (P < 0.05) suppressed by halothane (to 36% ± 15% at 1.2 MAC) but not isoflurane (Fig. 3C). Two-factor analysis revealed a significant (P < 0.01) difference between halothane and isoflurane for absolute windup over the 0.0–1.2 MAC range. Similarly, the slope of windup was significantly (P < 0.01) suppressed by halothane (to 22% ± 7% at 1.2 MAC) but not isoflurane (Fig. 3D). Two-factor analysis again revealed a significant difference in windup slope between anesthetics (P < 0.01) over the 0.0–1.2 MAC range.

For the step from 0.8 to 1.2 MAC, AUC windup was significantly suppressed by halothane (309 ± 64 to 180 ± 48 action potentials; P < 0.05) but not by isoflurane (310 ± 48 to 322 ± 66). Absolute windup was not significantly affected by halothane (97 ± 23 to 70 ± 22 action potentials) or isoflurane (181 ± 32 to 217 ± 46), although there was a significant difference between anesthetics (P < 0.01). Slope of windup was significantly suppressed by halothane (0.77 ± 0.17 to 0.34 ± 0.10 action potentials per 10 stimuli; P < 0.05) but not by isoflurane (1.21 ± 0.22 to 1.48 ± 0.43), and the difference between anesthetic effects was significant (P < 0.01). At 0.8 MAC, the median arterial blood pressures for halothane and isoflurane were 65 mm Hg (range, 50–150) and 81 mm Hg (range, 51–132); this difference was not statistically significant. At 1.2 MAC, arterial blood pressures for halothane and isoflurane were 54 mm Hg (range, 50–86) and 74 mm Hg (range, 50–122), respectively. The difference was statistically significant (P = 0.04; Mann-Whitney U-test).

The spontaneous firing of action potentials is shown in Figure 4A for windup cells. Halothane did not significantly affect spontaneous firing rates, whereas isoflurane significantly suppressed spontaneous firing (P < 0.01).

Figure 4.

Figure 4.

In two units, C-fiber-evoked responses were completely suppressed at 1.2, but not 0.8, MAC halothane. In another two cases, the unit was apparently lost during a shift in anesthetic concentration, but we cannot exclude the possibility that it was totally suppressed. Otherwise, there was no evidence that either anesthetic completely inhibited windup at sub-MAC concentrations.

Delayed windup, that is, an absence of C-fiber-evoked response to the initial 2–3 stimuli followed by reestablishment of windup, was observed in 2 units under isoflurane. Halothane did not produce delayed windup in any neurons.

In 13 experiments in which no windup cells were found, we tested anesthetic effects on flat neurons. Seven units were fully tested with both anesthetics and another two with isoflurane (another four were excluded because of incomplete testing or arterial blood pressure). The groups tested with halothane (n = 7) or isoflurane (n = 9) had mean slopes of −0.05 ± 0.19 and 0.11 ± 0.39, respectively, at 0 MAC; slopes did not change significantly when retested. The mean depth of the neurons in these groups was 458 ± 28 μm.

Figure 5 (A and B) plots mean responses of flat units versus stimulus number and shows a dose-dependent downward shift in the curves for both anesthetics. Although neither anesthetic significantly affected the initial response calculated as mean spike count, isoflurane significantly reduced the initial response (to 32% ± 13%) when calculated as a percent of the response at 0.0 MAC (Fig. 6A). AUC windup was significantly suppressed by halothane and isoflurane (P < 0.05 for both) in a concentration-dependent manner (Fig. 6B) to 42% ± 11% and 34% ± 8%, respectively, at 1.2 MAC. Halothane and isoflurane suppressed initial responses and AUC responses in two units exhibiting wind down. Although there was a trend for halothane and isoflurane to reduce spontaneous firing in the flat group, this did not reach statistical significance (Fig. 4B). Some neurons unexpectedly developed considerable spontaneous firing after returning from isoflurane to 0.0 MAC and before switching to halothane, possibly contributing to the higher spontaneous firing rates in the halothane group (Fig. 4B).

Figure 5.

Figure 5.

Figure 6.

Figure 6.

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The present results show that 1) halothane and isoflurane, over a range from 0.0 to 1.2 MAC, dose-dependently suppressed lumbar dorsal horn neuronal responses to a train of 1-Hz electrical pulses in decerebrated rats, except for windup during the step from 0.8 to 1.2 MAC isoflurane, and 2) most nociceptive neurons found at 0 MAC anesthesia continued to be responsive at 0.8 MAC. These findings are considered relative to the immobility produced by anesthetics.

Halothane and isoflurane at 0.8 MAC depressed AUC windup by 50% compared with 0 MAC. Increasing halothane from 0.8 to 1.2 MAC further suppressed AUC windup to 34% of control, whereas increasing isoflurane did not further suppress AUC windup. The progressive depression of dorsal horn nociceptive processing at sub-MAC concentrations could partly account for the increase in stimulus frequency and intensity required to produce movement as isoflurane increases from 0 toward 1.0 MAC (14) and for the decrease in movement during supramaximal stimulation as isoflurane increases from 0.6 to 0.9 MAC (21).

The present data are consistent with previous studies. Neuronal responses to a surgical incision were suppressed by 1.0 MAC of halothane and isoflurane to 47% and 66%, respectively, relative to 0 MAC in spinal-transected decerebrated rats (7). Neuronal responses to heat (51°C) were suppressed by 1.0 MAC of halothane to 33% of that during 0.0 MAC in spinal-transected decerebrated rats and by 1% inhaled halothane to 41% of that during 0.0 MAC in spinal-transected cats (5,6). In intact rats, neuronal responses to noxious heat or windup stimulation were consistently suppressed by 1.4 MAC of halothane and either enhanced or unchanged by 1.4 MAC of isoflurane, relative to 0.8 MAC (1,4). These data collectively indicate that halothane and isoflurane suppress nociceptive responses over a broad concentration range. The present study confirms and extends this by including concentrations between 0 and 1.2 MAC, and thereby showing a progressive dose-dependent antinociceptive effect.

In neurophysiologic studies with intact animals, neurons are typically selected under peri-MAC anesthetic conditions, i.e., 0.8–1.2 MAC. In the present study, selecting neurons during 0.0 MAC and evaluating responsiveness at 0.8–1.2 MAC provided an estimate of the population of neurons that might be missed by selecting at 0.8–1.2 MAC. A few units became unresponsive at 1.2 MAC. Nearly all units remained responsive at 0.8 MAC, and only a few exhibited delayed windup, suggesting that there are few if any dorsal horn neurons whose responses are completely depressed at sub-MAC anesthetic concentrations. These findings therefore argue against the hypothesis that abolished responsiveness of a substantial population of spinal dorsal horn neurons represents a mechanism underlying anesthetic-induced immobility.

Neuronal responses to repetitive C-fiber strength stimulation were assessed in several ways. AUC windup reflects the total nociceptive output of the neuron, consisting of the initial response plus windup per se, measured as absolute windup or the initial slope of the windup curve (3). Classification of windup neurons was verified by significant absolute windup and positive slope, whereas the responses of flat cells did not change across stimulus trials and had a slope near zero (Fig. 5). Over the 0–0.8 MAC range, both anesthetics reduced each measure of windup (Fig. 2; Fig. 3B–D), although depression of windup was significantly greater for halothane compared with isoflurane. In the step from 0.8 to 1.2 MAC, all measures of windup were suppressed by halothane but tended to increase with isoflurane, even though the initial response and spontaneous activity were further depressed. Conceivably, the significantly lower arterial blood pressure at 1.2 MAC of halothane compared with isoflurane might have contributed to this difference. However, the present results with decerebrated rats are fully consistent with previous data from intact rats showing unchanged (2) or increased windup (4) in the step from 0.8 to 1.2 MAC of isoflurane, whereas the same step increase in the halothane concentration further reduced windup.

Halothane and isoflurane were equipotent in dose-dependently reducing the initial response (Fig. 3A) and flat responses (Fig. 5). These results indicate that halothane and isoflurane are equally effective in reducing neuronal excitation evoked at C-fiber latency and evident as the initial response, yet halothane is more effective than isoflurane in reducing windup per se across a broad concentration range, and especially in the 0.8–1.2 MAC range. Conversely, isoflurane was more effective in depressing spontaneous activity compared with halothane (Fig. 4), also consistent with earlier studies (4).

From a clinical point of view, some surgical procedures or common practices, such as suturing a wound, can be associated with repetitive noxious stimulation and might be expected to produce windup. Windup usually dissipates within minutes (11), although it has been associated with signs of central sensitization such as increased neuronal receptive field size (12). Central sensitization represents an increase in excitability of nociceptive neurons and is associated with more persistent hyperalgesia. The present results show that halothane and isoflurane depress windup, even at sub-MAC concentrations, that would be beneficial in reducing the chance for the repetitive noxious input to produce central sensitization and hyperalgesia.

The large proportion of flat responding neurons during 0.0 MAC was unexpected and might reflect increased tonic descending inhibition in the decerebrated unspinalized preparation, as compared with intact anesthetized animals (23,24). Flat responding neurons have been infrequently reported in previous in vivo and in vitro studies (4,25,26). Although these neurons do not windup, they respond to C-fiber input and hence would be expected to contribute to nociceptive processing. Hence, anesthetic depression of these units may also contribute importantly to anesthetic-induced immobility.

In summary, spinal dorsal horn neuronal windup is dose-dependently suppressed by isoflurane and halothane over a range of 0.0–1.2 MAC in the decerebrated rat, except during the step from 0.8 to 1.2 MAC of isoflurane. These findings support the concept that isoflurane and halothane provide concentration-dependent antinociceptive effects on lumbar dorsal horn neurons. There are few, if any, anesthetically vulnerable neurons that might be missed when selecting neurons near MAC.

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The authors thank Dr. Shawn G. Hayes for assistance in learning the preparation.

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