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ANESTHETIC PHARMACOLOGY

Hexafluorobenzene Acts in the Spinal Cord, Whereas O-Difluorobenzene Acts in Both Brain and Spinal Cord, to Produce Immobility

From the Department of Anesthesiology and Pain Medicine, University of California, Davis, California.

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

	Abstract

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BACKGROUND: Previous work demonstrated that isoflurane and halothane act on the spinal cord rather than on the brain to produce immobility in the face of noxious stimulation. These anesthetics share many effects on specific receptors, and thus do not test the broad applicability of the mediation of immobility by the cord. We sought to test such an applicability by determining whether the cord mediated the immobilizing effects of two aromatic anesthetics that differ greatly in their ability to block N-methyl-d-aspartate receptors.

METHODS: We investigated the actions of hexafluorobenzene (HFB) and o-difluorobenzene (ODFB) using an intact goat model that allowed selective delivery of anesthetics to the brain. Because our results suggested a significant cerebral effect of ODFB, in other goats we administered halothane 0.5% to the brain, while determining the ODFB concentration delivered to the body (the cord) required for immobility. We chose halothane because the present and previous studies found that cerebral halothane concentrations alone required for producing immobility far exceeded those required in the cord. We also applied the above techniques to another benzene-containing anesthetic, propofol.

RESULTS: Prebypass minimum alveolar concentration (MAC) for HFB was 0.82% ± 0.14% (mean ± sd); increased to 2.04% ± 0.8% (P < 0.01) during selective delivery to the cranial circulation; and returned to 0.79% ± 0.28% postbypass. Corresponding values for ODFB were 0.46% ± 0.07%, 0.63% ± 0.12% (P < 0.05), and 0.44% ± 0.10%. ODFB MAC was 0.32% ± 0.17% during selective halothane delivery to brain. But when ODFB was administered to the whole body, MAC was 0.37% ± 0.05%, (NS). Like HFB, the halothane requirement increased threefold when delivered only to the head. In four of five animals, propofol requirements increased by 240%, but in one animal propofol requirements decreased, and the overall change was not statistically significant.

CONCLUSIONS: These data suggest that HFB, like halothane, produces immobility, predominantly by a spinal cord action, and that HFB differs from ODFB with respect to brain versus spinal sites of action. Nonetheless, although ODFB can produce immobility via a cerebral action, it also can do this via an independent action in the spinal cord. Thus, our results continue to support the spinal cord as the primary site at which inhaled anesthetics, and perhaps propofol, produce immobility.

	Introduction

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Immobility is a defining mark of general anesthesia. Several lines of evidence suggest that the spinal cord mediates immobility. Anesthetic requirements to produce immobility increase two- to fourfold when isoflurane or halothane is delivered solely to the brain rather than to brain and torso (1,2); thiopental requirements increase twofold (2). In rats, decerebration does not change isoflurane MAC (minimum alveolar concentration) (3).

Whether this notion of the importance of the cord applies to all inhaled anesthetics is unknown. Caution regarding such an interpretation follows from a recognition of the similarity of receptor actions of all the three test anesthetics: for example, halothane, isoflurane, and thiopental all enhance the action of GABA (-aminobutyric acid) on GABA_A (GABA-type A) receptors while having minimal blocking effects on N-methyl-d-aspartate (NMDA) receptors (4,5).

The present study sought to test this notion by measuring the cerebral versus spinal cord immobilizing effects of two inhaled compounds (hexafluorobenzene [HFB] and ortho-difluorobenzene [ODFB]) that differed widely in their receptor effects. At MAC, HFB minimally affects the NMDA receptor whereas ODFB causes significant depression (6). NMDA receptors exist throughout the central nervous system. Furthermore, HFB enhances the effect of GABA on GABA_A receptors, while ODFB has smaller effects on the GABA_A receptor (unpublished data of DER). We postulated that selective delivery of these anesthetics to the brain and spinal cord would reveal differences between the brain and spinal cord with respect to anesthetic-induced immobility mediated by the NMDA receptor, as well as the GABA_A receptor This would test the present hypothesis (1–3) that a spinal site of anesthetic action applies broadly. Thus, we predicted that HFB and ODFB would behave like other volatile anesthetics in that, when selectively delivered to the brain, anesthetic requirements to produce immobility would increase several fold with both anesthetics.

	METHODS

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The Animal Care and Use Committee at the University of California, Davis approved this study. Goats (four males and 19 females, weight 46 ± 11 kg) were anesthetized by mask with desflurane and the trachea intubated. A 14-gauge IV catheter was inserted percutaneously in a cephalic vein and cephazolin (1 g) administered IV. Rectal temperature was measured and maintained at 37.4°C ± 1.1°C using a heating lamp and blankets, as needed. The carotid arteries and jugular veins were isolated, as previously described (2). The occipital arteries, which act as an anastomosis between the carotid and vertebral arteries, were isolated and ligated; this maneuver prevents blood from a carotid artery flowing to the brain via the vertebral arteries. The vertebral arteries in the goat normally do not contribute to the cerebral circulation (7).

The electroencephalogram (EEG) was monitored from small steel screws placed directly into the skull through small scalp incisions. In most animals, we used a bilateral hemispheric montage in which the active leads were 2 cm from the midline over the center of the posterior skull. The ground electrode was placed in the midline near the front of the skull. In some animals, we monitored each hemisphere separately, with active electrodes placed 2 cm from midline, one near the front of the skull and the other near the back, with a similar placement of two other electrodes on the other side of the skull. The raw EEG signals were amplified and digitized (1000 samples/s) and stored on computer using Chart5 software (ADInstruments, CO Springs, CO). The EEG data (1 min samples) at the anesthetic concentrations that permitted movement and prevented movement were filtered at 1–50 Hz and total power was determined using the spectrum function of the Chart5 software.

Seven goats received HFB and five received ODFB. The test anesthetic was introduced using a vaporizer in line with the fresh gas inflow. For ODFB we used a vaporizer designed for halothane, whereas for HFB we used an enflurane vaporizer. HFB and ODFB have blood-gas solubilities of approximately 2.5 and 9, respectively (8), limiting their rate of rise in the alveoli. We slowly decreased the desflurane concentration as the alveolar concentration of the test anesthetic increased. We waited at least 45 min before testing MAC, with the last 20–25 min of that time having a stable end-tidal concentration of the test anesthetic, and with a desflurane concentration at <5%–10% of its initial concentration. End-tidal gas samples (30 mL) were drawn into glass syringes and anesthetic concentrations analyzed with a Gow-Mac gas chromatograph (Gow-Mac Instrument, Bridgewater, NJ) equipped with a flame ionization detector to measure concentrations of test compounds and desflurane or halothane at intervals, particularly immediately before stimulation of the goat. The 4.6 m long, 0.22 cm (ID) column was packed with SF-96. The column temperature was 100°C. The detector was maintained at temperatures approximately 50°C warmer than the column. The carrier gas was nitrogen at a flow of 15–20 mL/min. The detector received 35–38 mL/min hydrogen and 240–320 mL/min air. Primary standards were prepared for each compound, and the linearity of the response of the chromatograph determined. We also commonly used secondary (cylinder) standards referenced to primary standards.

After IV administration of heparin (5000 U), the right carotid artery was ligated and a catheter was placed into the artery and directed toward the heart, thus permitting measurement of mean arterial blood pressure (MAP) and withdrawal of blood for acid–base analysis. Arterial blood was withdrawn (400–600 mL) to be used for later priming of the oxygenator; heparin (10,000 U) was added to the collection bag before withdrawal. Heparin was administered IV (initial dose 400 U/kg then 200 U/kg every 2 h).

A cannula was placed into the right carotid artery (directed toward the head) (9). A Y cannula was placed into the right jugular vein, permitting cranial venous blood to be drained to either the torso or to an oxygenator. A single cannula was placed into the left jugular vein to permit drainage of cranial venous blood to the oxygenator; this line was clamped off when the bypass was not in use, during which times cranial venous blood drained into the torso only via the Y cannula. A 20-gauge catheter (4.5 cm length) placed into the left carotid artery and directed toward the head permitted measurement of cranial arterial pressure during cranial bypass.

For stimulation, we applied a clamp (12 in. hemostat, full ratchet lock) to a dew claw on a hindlimb, and oscillated (1 Hz) the clamp for 60 s, or until the animal displayed gross and purposeful movement, usually consisting of pawing motions of another extremity or turning of the head toward the stimulus. Straining, coughing, or withdrawal of the stimulated extremity was considered nonpurposeful movement. When the movement was equivocal, the stimulus was applied again 1–2 min later. If the animal displayed movement, the anesthetic concentration was increased by about 20%–30% of its value. Alternatively, if movement was absent the anesthetic concentration was decreased by 20%–30%. This new concentration was maintained for at least 20–25 min by checking the end-tidal samples three to four times over the period of equilibration. We reapplied the noxious stimulus and repeated this process until two concentrations were found that just permitted and just prevented movement. The arithmetic mean of those two concentrations was MAC. We used relatively large concentration adjustments because our hypothesis was that selective delivery would substantially increase anesthetic requirements, and thus more precise determination of MAC was not needed, and also because this minimized anesthesia time, applications of the noxious stimulus and time on bypass.

After prebypass (control) MAC was determined, we established cranial bypass as described previously (1). The bubble oxygenator (adult size, Braile Biomedica, Sao José do Rio Preto, Brazil) was primed with the goat's blood. The gas flow to the oxygenator was 97% oxygen and 3% carbon dioxide. A vaporizer was placed in line with the gas flow to permit selective anesthetic delivery to the cranial circulation. Care was taken to eliminate air bubbles from the arterial line of the bypass circuit; an arterial filter was not used. The venous cannulae were attached to the venous drainage of the oxygenator and the arterial blood was withdrawn with a roller pump (Sarns, Ann Arbor, MI). Plastic tubing (3/8 in. outside diameter; NovaSci, The Woodlands, TX) was used. Pressure on the arterial side of the circuit was measured from an access port. The tubing conveying arterial blood from the roller pump was attached to the carotid cannula. Cranial bypass was slowly initiated by clamping the venous drainage to the torso, and permitting the cranial venous blood to drain into the oxygenator. The roller pump was started and arterial blood from the oxygenator infused into the cranial circulation, thereby establishing partial bypass. Blood flows from the bypass were 300–500 mL/min. Once there appeared to be adequate venous drainage (5–10 min), complete cranial bypass was accomplished by placing a temporary ligature around the left carotid artery such that the head was perfused only by the bypass unit. Cranial temperature was measured with a nasopharyngeal temperature probe and maintained at 37.4°C ± 1.1°C during bypass using the heating system (water bath) of the oxygenator. Anesthetic delivery to the torso was discontinued and the end-tidal concentrations of the experimental anesthetic were determined several times over the next 40 min to ensure that they were <10% of their original values. Cranial anesthetic concentration was determined for samples withdrawn from the exhaust of the oxygenator. We waited at least 30 min to permit stable anesthetic concentrations in the cranial bypass system. We then repeated the application of the noxious stimulus, as described earlier, to determine anesthetic requirements on bypass. We adjusted the anesthetic concentration to the head, waiting 20–30 min for equilibration before reapplication of the noxious stimulus. We continued this process until we found the concentrations that just permitted and just prevented movement.

After determination of anesthetic requirements during bypass, we readministered the experimental anesthetic to the lungs, removed the temporary ligature from the left carotid artery, and discontinued bypass. The cranial venous blood was permitted to drain into the torso, thus establishing normal circulation. After waiting 30–45 min to permit stable equilibration of the experimental anesthetic, MAC was determined again, as described earlier for the control MAC.

We examined halothane requirements in a third group (n = 3) to make a direct comparison to the ODFB and HDB groups and to previous studies of halothane (2). These animals were anesthetized with halothane, and end-tidal halothane concentrations were determined using a calibrated Rascal II agent analyzer (Salt Lake City, UT). The control MAC was determined, and bypass then initiated. During bypass, halothane was added to the oxygenator gas flow via an in line halothane vaporizer, torso delivery of halothane was discontinued, and the end-tidal concentrations permitted to decrease to <0.2%. The exhaust of the oxygenator was monitored with the agent analyzer and the halothane concentrations adjusted until two concentrations were found that just permitted and just prevented movement in response to noxious stimulations. Bypass was discontinued, normal circulation was re-established and postbypass MAC was determined.

Our initial results showed that ODFB requirements only modestly increased (35%) when it was selectively delivered to the head, suggesting that ODFB might act primarily in the brain to suppress movement. This finding did not exclude the possibility that ODFB also might act in the spinal cord independent of a cerebral action. Thus, we examined ODFB requirements in three goats that had halothane 0.5% delivered to the cranial circulation while ODFB was delivered to the torso. We reasoned that this halothane concentration would produce unconsciousness (and prevent prolonged spontaneous movement) yet would be insufficient, by itself, to prevent immobility in response to noxious stimulation (2). We hypothesized that if ODFB acted only in the brain, then ODFB requirements in the torso would increase substantially. In these animals, anesthesia was induced with desflurane, and changed to ODFB as described above. After control ODFB MAC was determined, bypass was initiated and halothane added to the cranial circulation via a halothane vaporizer that was in line with the gas flow to the oxygenator. The ODFB in the torso (end-tidal) and the halothane concentration in the head (oxygenator exhaust) were determined using gas chromatography. We waited 30–40 min for the ODFB concentrations in the head to decrease to <10% of the initial values, after which we determined ODFB MAC (from end-tidal samples). Postbypass MAC for ODFB was determined.

Like HFB and ODFB, propofol contains an aromatic ring. We were interested in determining what relationship this structural characteristic might have to brain and spinal cord sites of action. Five goats were anesthetized with desflurane and prepared for cranial bypass as described above. Once the surgical procedures were completed, propofol was administered (2 mg/kg bolus followed by continuous IV infusion 300 µg · kg^–1 · min^–1) and administration of desflurane was discontinued. After waiting 15–20 min (end-tidal desflurane concentration <1%), we applied the noxious stimulus to the dew claw to elicit movement. Five minutes before stimulation, and at the time of stimulation, a 3 mL arterial blood sample was obtained for analysis of the propofol plasma concentration using gas chromatography (10). In brief, a 1 mL blood sample was added to chloroform (1 mL) which had undecane (50 µg/mL) added as an internal standard. The mixture was vigorously agitated for 30–60 s and then centrifuged. A 1 µL sample (calibrated syringe, Hamilton Syringe Company, Reno, NV) of the propofol extracted into chloroform was injected into a gas chomatograph (Varian, Walnut Creek). A standard curve was developed (0–100µg/mL range, correlation r = 0.99) and the peaks compared to the standard curve.

Propofol infusion rates were increased or decreased (depending on the response to clamping of the dew-claw) by 25%–30% and after a 15–20 min equilibration period the clamp was reapplied. Once control propofol requirements were determined we established bypass, and infused propofol into the bypass unit (venous side) at about 10% of the rate used for the whole body. Propofol administration to the torso was discontinued, and the cranial infusion rate adjusted to determine cranial propofol requirements; we waited 15 min between changes to permit equilibration. At each stimulus, a blood sample was obtained from the arterial limb of the bypass circulation and plasma propofol concentration determined. Once propofol requirements were determined, bypass was discontinued, propofol administered to the entire body, and postbypass propofol requirements determined.

Of 23 animals, three had initial low venous return. For these animals, we waited until bypass had stabilized for at least 10–15 min before MAC determination. In three other animals with low venous return, we needed to use systemic arterial blood to help maintain adequate blood volume in the oxygenator. In two of these animals, MAC testing was performed at least 10 min after the use of systemic blood. The third animal in which systemic blood was needed during MAC testing was anesthetized with ODFB to the torso and halothane to the head. The ODFB concentration in the bypass exhaust, however, was only 10% of that in the torso. Thus, the addition of systemic blood to the bypass likely did not significantly affect the MAC data.

Data are presented as means and sd. The MAC data were evaluated using repeated measures analysis of variance, followed by post hoc testing with the Student–Newman–Kuels test. Because no significant changes occurred in MAC pre- versus postbypass, we averaged these values and used the average for comparison to the bypass MAC. We compared the change in MAC during cranial delivery between HFB and ODFB by comparing the ratios of the bypass MAC to the control MAC using the Student's t-test. The EEG total power (sub-MAC versus supra-MAC) was compared using the Student's t-test. A P < 0.05 was considered significant.

	RESULTS

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HFB requirements increased nearly threefold during selective delivery to the cranial circulation (267% ± 110% of control, P < 0.05; Table 1). In two HFB goats, we could not obtain MAC postbypass because of hemorrhage and hypotension. ODFB requirements modestly increased (140% ± 23% of control, P < 0.05) during selective cranial delivery. The increase in HFB requirements differed significantly from that occurring with ODFB (P < 0.05, unpaired t-test). Halothane requirements increased 295% ± 50% (P < 0.05, Table 1). When halothane 0.5% was delivered to the cranial circulation, ODFB requirements in the torso did not differ significantly from ODFB requirements for the body as a whole. In four of five animals, propofol requirements increased to 240% of control during bypass, but in one animal propofol requirements decreased, and the overall change was not statistically significant (Table 1).

The EEG remained active during the control, bypass, and postbypass periods. Only one animal (anesthetized with HFB) appeared to have prolonged EEG depression that began toward the end of bypass and extended into the postbypass period. However, this animal's postbypass MAC (1.24%) was not depressed when compared with its prebypass MAC (0.97%). Although some of the animals anesthetized with HFB and ODFB had muscle twitching, no overt EEG evidence of seizure activity was observed. The EEG total power was not significantly affected by increasing the anesthetic concentration (Table 2). The systemic MAP was 101 ± 26 mm Hg during the prebypass and postbypass periods. During bypass, the systemic MAP was 116 ± 27 mm Hg, while the cranial MAP was 58 ± 17 mm Hg. Postbypass, when the MAP measured from the left carotid artery was 86 ± 12 mm Hg, it was 58 ± 12 mm Hg measured from the arterial bypass cannula in the right carotid artery, indicating a pressure gradient across the rete mirabile. Thus, the actual cranial blood pressure during bypass was likely 25–30 mm Hg higher than the recorded values. Arterial blood pH was 7.35 ± 0.07, Paco₂ was 37 ± 7 mm Hg, Pao₂ was 528 ± 96 mm Hg, and glucose was 124 ± 45 mg/dL.

	DISCUSSION

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We found that selective delivery of HFB or halothane, but not ODFB, to the head substantially increased anesthetic requirements. These data suggest that HFB, like halothane and isoflurane, acts predominantly in the spinal cord, while ODFB can act in the brain to produce immobility. Furthermore, when 0.5% halothane was administered to the head, ODFB requirements were unchanged from control values, suggesting that ODFB can produce anesthesia by an action on the spinal cord independent of an action on the brain. Propofol requirements did not change significantly, although in four of five animals requirements increased during selective delivery.

The results of the experiments by Antognini et al. (1,2) and Rampil et al. (3) indicated that the spinal cord rather than higher centers mediate the capacity of inhaled anesthetics to cause immobility. However, those experiments tested this paradigm with only two volatile anesthetics, halothane and isoflurane. These anesthetics share many properties, including similar effects on major receptors responsible for excitatory and inhibitory transmission. Thus, they may be viewed as but one anesthetic, and the issue of the generalizability of the Antognini et al. and Rampil et al. results might be questioned. Do the results apply broadly to all inhaled anesthetics, particularly to anesthetics with different receptor effects? Accordingly, the present study asked whether anesthetics that differed from halothane-isoflurane in receptor effects or were similar to halothane-isoflurane in receptor effects would produce findings similar to or different from those found by Antognini et al. for halothane and isoflurane (1,2).

We chose HFB and ODFB as our test inhaled anesthetics for two reasons. First, ODFB differs from halothane or isoflurane in being a much more potent blocker of NMDA receptors at MAC (6). Second, fluorinated benzenes appear to differ from conventional anesthetics in their relationship between potency as blockers of NMDA receptors and the importance of such blockade to MAC (11). For the benzenes, a correlation is found (greater blockade correlates with a decreasing effect on MAC of adding an NMDA blocker such as MK-801); for conventional anesthetics, a correlation is not found (the effect of administration of MK-801 on MAC is the same for conventional inhaled anesthetics that are and are not potent blockers of NMDA receptors). Thus, one prediction was that HFB would produce results similar to those found with halothane. This prediction was supported by the present results (Table 1).

HFB and ODFB also appear to have differing potencies at the GABA_A receptor (unpublished data): HFB, more than ODFB, enhances the action of GABA at the GABA_A receptor. Effects of ODFB and HFB on the glycine receptor are unknown. Glycine is an important inhibitory neurotransmitter, especially in the spinal cord, thus we cannot exclude the possibility that the differences we observed in the present study were due to effects at the GABA_A receptor or at the glycine receptor. Although other anesthetics have predominant actions at the NMDA receptor (i.e., N₂O and xenon) practical factors (need for hyperbaric conditions with N₂O and xenon plus the expense of xenon) prevented us from using these anesthetics. In addition, selective delivery of MK-801, a noncompetitive blocker of the NMDA receptor, might help to elucidate the spinal and supraspinal contributions of the NMDA receptor to anesthetic action. Lastly, anesthetic effects on a receptor system are determined using a reduced system, such as receptors expressed in frog oocytes, and thus it is unclear to what extent anesthetic effects at these receptors reflect anesthetic actions in vivo.

It would at first appear that the notion that the spinal cord as a site of anesthetic action is not generalizable, ODFB providing an exception. However, the finding that the bypass MAC with ODFB only modestly (140% of control rather than 240% or 300%) exceeded MAC when ODFB was delivered to both cord and brain does not exclude mediation by the cord. ODFB might affect both the cord and brain, whereas HFB and halothane might affect only the cord. That is, some compounds might influence the brain in a manner that could affect MAC while others might not, but this influence would not exclude a separate influence on the cord.

To test whether the cord still might be important to the immobility (MAC) produced by ODFB, we measured MAC during delivery of a low concentration (approximately 0.5 MAC) of halothane to the brain concurrent with delivery of ODFB to the cord. We assumed that 0.5% halothane would not produce immobility because 300% of MAC is needed to produce immobility when halothane is delivered to the brain and no anesthetic is delivered to the cord (see Ref. 2 and the present results). The cord requirement for ODFB did not increase when ODFB was delivered to the cord while the brain received 0.5 MAC halothane (Table 1). Thus the importance of the spinal cord as a site of anesthetic action still stands: the spinal cord remains as the primary/universal mediator of the capacity of inhaled anesthetics to produce immobility.

Nonetheless, some anesthetics might have important actions in the brain that could influence MAC, including seemingly paradoxical actions. For example, there is evidence that isoflurane modulates nociception at a brainstem site. When low isoflurane concentrations are selectively delivered to the intact brain, MAC in the torso is lower than expected (12). Second, ablation of brainstem noradrenergic neurons increases the potency of isoflurane to depress tail flick response to noxious stimulation (13). Third, chronic spinal cord transection also increases isoflurane potency (14), although these data stand in contradistinction to those of Rampil (15). The present data and our previously published data indicate that anesthetics can act in the brain (albeit weakly, except for ODFB) to suppress movement in response to noxious stimulation, thus suggesting that anesthetics might have dual actions in the brain, with facilitation of nociceptive responses at low anesthetic concentrations, but suppression at higher concentrations.

Where might ODFB act in the brain, and what neural pathway(s) would mediate immobility? Our results suggest that ODFB can act in either the brain or spinal cord, and an action at either site, independent of the other (e.g., without synergy or additivity), can produce immobility. Nakazato et al. (16) reported that CP-101,606, a noncompetitive antagonist that acts selectively on NMDA receptors containing the NR2B subunit, acts in the brain, but not spinal cord, to produce analgesia. Furthermore, Cruz et al. (17,18) found that toluene, a benzene derivative, noncompetitively inhibited this NMDA receptor subtype with far greater potency than it did other NMDA receptor subtypes. Thus, we speculate that ODFB might act at NMDA receptors containing the NR2B subunit in the brain to produce analgesia, which contributes to the immobilizing action of ODFB. An action in the brain presumably would either cause descending inhibition of dorsal horn neurons, central pattern generators, motoneurons, or some combination of these possibilities. Selective delivery of ODFB to the brain, while recording from these different neuronal populations, might elucidate the specific pathway. HFB, which is less potent than ODFB at inhibiting NMDA receptors containing the NR2B subunit (6), would be expected to have less effect in the brain than ODFB.

The benzene ring distinguishes ODFB and HFB from conventional inhaled anesthetics. Accordingly, we asked if the brain or spinal cord mediates the immobility produced by propofol, a benzene-based anesthetic. For our combined results, delivery of propofol primarily to the brain increased MAC by 100%. However, results in one of five goats were more than two standard deviations from the four other goats. If the data from this deviant goat are excluded, delivery of propofol primarily to the brain increased MAC by 140%. We are inclined to believe this value. That also is consistent with a considerable effect of propofol on GABA_A receptors with little effect on NMDA receptors (i.e., propofol resembles halothane, isoflurane, and HFB). But if we believe the 100% result, then propofol acts like ODFB, despite radically different receptor effects. Nelson et al. (19) found that propofol requirements for sedation in rats increased when gabazine, a GABA_A receptor antagonist, was injected into the tuberomammilary nucleus, suggesting a discrete brain site of anesthetic action for sedation. But these investigators did not examine responses to noxious stimulation, however, so it is unknown whether propofol produces immobility (in response to intense noxious stimulation) at a brain site.

In summary, we report that the MAC of HFB increased substantially when HFB was selectively delivered to the brain. In contrast, the MAC of ODFB only modestly increased during selective delivery. However, as demonstrated by the combination of halothane to the head and ODFB to the torso, ODFB can act in the spinal cord, independent of its action in the brain, to produce immobility. The site within the spinal cord where inhaled anesthetics act to produce immobility remains unknown. In addition, at least one inhaled anesthetic can act within the brain to produce immobility, and this site, too, remains unknown.

	Footnotes

 
Accepted for publication November 21, 2006.

Supported by National Institute of Health Grants 1PO1GM47818, R01-GM57970, R01-GM61283, and RO1-GM61927.

Dr. Eger is a paid consultant to Baxter Healthcare Corp. Baxter Healthcare Corp. donated the desflurane used in these studies.

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Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

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