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Anesth Analg 2002;95:573-577
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Nonhalogenated Anesthetic Alkanes and Perhalogenated Nonimmobilizing Alkanes Inhibit {alpha}4ß2 Neuronal Nicotinic Acetylcholine Receptors

Douglas E. Raines, MD*{dagger}, Robert J. Claycomb, BS{dagger}, and Stuart A. Forman, MD PhD*{dagger}

Departments of Anesthesia, *Harvard Medical School; and {dagger}Massachusetts General Hospital, Boston, Massachusetts

Address correspondence and reprint requests to Dr. D. E. Raines, Department of Anesthesia, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114. Address e-mail to draines{at}partners.org


   Abstract
Top
 Abstract
Introduction
 Materials
 Methods
 Results
 Discussion
 References
 
The nonhalogenated anesthetic alkanes, cyclopropane and butane, do not enhance {gamma}-aminobutyric acid-elicited GABAergic currents, suggesting that these agents produce anesthesia via interactions with other molecular targets. Perhalogenated nonimmobilizing alkanes, such as 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane, also fail to enhance GABAergic currents, but display specific behavioral effects that are distinct from those of structurally similar anesthetics. At concentrations predicted to be anesthetic, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane produce amnesia but fail to produce immobility. Neuronal nicotinic acetylcholine (nACh) receptors are sensitive to many anesthetics and are thought to have an important role in learning and memory. We postulated that neuronal nACh receptors might mediate the common amnestic action of nonhalogenated and perhalogenated alkanes. To test the hypothesis that neuronal nACh receptors have a role in mediating the behavioral effects of general anesthetics and nonimmobilizers, we quantified the inhibitory potencies of nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes on currents mediated by {alpha}4ß2 neuronal nACh receptors. Our studies reveal that anesthetics and nonimmobilizers significantly inhibit {alpha}4ß2 neuronal nACh receptors at concentrations that suppress learning and with potencies that correlate with their hydrophobicities. These results support the hypothesis that {alpha}4ß2 neuronal nACh receptors mediate the amnestic actions of alkanes but not their immobilizing actions.

IMPLICATIONS: The results of this study suggest that the immobilizing actions of general anesthetics do not result from the inhibition of {alpha}4ß2 neuronal nicotinic acetylcholine receptors. However, the inhibition of neuronal nicotinic acetylcholine receptors may account for the amnestic activities of general anesthetics and nonimmobilizers.


   Introduction
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 Abstract
 Introduction
Materials
 Methods
 Results
 Discussion
 References
 
General anesthetics, representing a wide range of chemical classes, induce a constellation of clinical behaviors, most notably immobility, unconsciousness, analgesia, and amnesia. Although the receptor targets responsible for these actions remain undefined, the {gamma}-aminobutyric acid type A (GABAA) receptor is widely believed to be an important site of anesthetic action, and many anesthetics potentiate agonist actions on this receptor (1). However, we have recently demonstrated that the nonhalogenated anesthetic alkanes cyclopropane and butane fail to enhance GABA-elicited GABAergic currents at pharmacologically relevant concentrations, suggesting that these agents exert their behavioral effects via interactions with other targets (2).

A group of perhalogenated alkanes have been identified that also fail to enhance GABA-elicited GABAergic currents at pharmacologically relevant concentrations (3,4). These compounds, referred to as nonimmobilizers, are of interest because they fail to inhibit movement in response to a noxious stimulus even at concentrations that are predicted to do so on the basis of their oil solubilities by the Meyer-Overton rule (3). However, nonimmobilizers are not inert because they can suppress learning (an action that they share with anesthetics) and induce convulsions (5,6). It has been suggested that nonimmobilizers may be useful pharmacologic tools for testing whether a particular site of action or molecular mechanism is likely to be responsible for a specific behavioral endpoint such as immobility or amnesia (3).

Neuronal nicotinic acetylcholine (nACh) receptors are cation-selective ligand-gated ion channels (7). Although their physiologic roles are not completely clear, it is thought that they contribute to a wide range of brain activities including learning, memory, and analgesia (8–10). The predominant nACh receptor subtype in neurons is believed to be composed of {alpha}4 and ß2 subunits (11). Electrophysiologic studies of {alpha}4ß2 neuronal nACh receptors have shown that they are potently inhibited by halothane, isoflurane, and sevoflurane, suggesting that they may mediate some of the in vivo actions of general anesthetics (12,13). We have previously reported that nonimmobilizers inhibit muscle-type nACh receptors (14), but two previous studies to assess the effects of nonimmobilizers on neuronal nACh receptors failed to reach a consensus (15,16).

The purpose of this study was to quantify the inhibitory potencies of nonhalogenated anesthetic alkanes and perhalogenated nonimmobilizing alkanes on currents mediated by {alpha}4ß2 neuronal nACh receptors expressed in Xenopus oocytes. We hoped that such studies might provide useful insights into the potential roles that neuronal nACh receptors have in mediating the behavioral actions of anesthetics and nonimmobilizers.


   Materials
Top
 Abstract
 Introduction
 Materials
Methods
 Results
 Discussion
 References
 
Cyclopropane and butane were purchased from Aldrich Chemical Co. (Milwaukee, WI), 1,2-dichlorohexafluorocyclobutane (F6), and 2,3-dichlorooctafluorobutane (F8) were from Lancaster Synthesis (Pelham, NH), isoflurane was from Baxter Healthcare Corp. (Deerfield, IL), and acetylcholine was from Sigma Chemical Co. (St. Louis, MO).


   Methods
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 Abstract
 Introduction
 Materials
 Methods
Results
 Discussion
 References
 
Molecular Biology Procedures
cDNAs for the rat {alpha}4ß2 neuronal nACh receptor subunits were gifts from James Patrick, PhD (Salk Institute, La Jolla, CA) and were subcloned into pSP64T. cDNAs for the human {alpha}4ß2 neuronal nACh receptor subunits were gifts from Jon Lindstrom, PhD (University of Pennsylvania, Philadelphia, PA). mRNAs were synthesized in vitro from linearized cDNA using commercial kits (Ambion, Auston, TX).

Xenopus Oocyte Expression
Xenopus laevis oocytes were surgically removed from frogs anesthetized with ice-cold tricaine and then placed in OR-2 solution (in mM: 82 NaCl, 2 KCl, 1 MgCl2, 5 HEPES; pH 7.6). After a 1–2 h incubation in collagenase D (1 mg/mL) to remove the follicular layer, stage 4 and 5 oocytes were selected for injection with a 1:1 mixture of mRNA encoding for the {alpha}4 and ß2 neuronal nACh receptor subunits. After injection, oocytes were allowed to incubate for at least 24 h in ND-96 buffer (in mM: 96 NaCl, 2 KCl, 1 CaCl2, 0.8 MgCl, 5 HEPES; pH 7.6) with 5 U/mL penicillin and 5 µg/mL streptomycin at 17°C before electrophysiologic studies.

Electrophysiology
All experiments were performed at room temperature (20°–22°C). Oocytes were placed in a 0.1-mL chamber and impaled at the animal pole with two capillary glass electrodes filled with 3 M KCl and possessing open tip resistances of 0.2–2 M{Omega}. Oocytes were voltage clamped at -50 mV by using a GeneClamp 500B amplifier (Axon Instruments, Foster City, CA). Perfusion of oocytes (4 mL/min) with the desired drug in Ca2+-free ND-96 buffer (Ca2+ replaced with Mg2+) was controlled by using a 6-channel valve controller (Warner Instruments, Hamden, CT) interfaced with an Axon Digidata card and driven by a personal computer using Axon’s pClamp 8.0 software. The perfusion apparatus was made from glass gas-tight syringes and Teflon tubing to minimize absorptive and evaporative loss of anesthetics and nonimmobilizers. In parallel experiments, gas chromatographic analysis of solutions exiting the perfusion system and entering the oocyte chamber indicated that such loss was <15%. Buffer solutions containing the desired con-centrations of anesthetic or nonimmobilizer were prepared by dilution of saturated solutions into buffer within a closed, air-free system with gas tight-syringes. Saturated solutions of isoflurane, cyclopropane, butane, F6, and F8 were taken as 15 mM, 10.6 mM, 1.1 mM, 225 µM, and 35 µM, respectively. Partial pressures were converted to aqueous concentrations using the appropriate aqueous/gas partition coefficient. The minimum alveolar anesthetic concentration (MAC) of nonimmobilizers predicted by the Meyer-Overton rule (MACpredicted) was defined as 1.82 atm/oil/gas partition coefficient (3).

In each experiment, the control current was first determined by perfusing the oocyte with buffer containing acetylcholine (1 mM for receptors composed of rat subunits and 2 µM for those composed of human subunit) for 30 s and measuring the peak current. The effect of anesthetic or nonimmobilizer was then assessed after a 5-min recovery period by perfusing the oocyte with buffer containing the anesthetic or nonimmobilizer for 30 s immediately followed by buffer containing the anesthetic or nonimmobilizer plus acetylcholine for 30 s to elicit current. After another 5-min recovery period, the control current was measured again to assure reversibility. The control current was then quantified as the average of the peak currents recorded during the two control experiments.

Concentration-response curves were generated by plotting the peak current in the presence of anesthetic or nonimmobilizer normalized to the control peak current. Each data point represents the mean of at least three measurements obtained using different oocytes and the error bars indicate the standard deviation from the mean. Statistical significance from control values was assessed by using a paired t-test with P < 0.05 considered significant. Data points were fit to a Hill equation by using Igor Pro 4.01 (Wavemetrics Inc., Lake Oswego, OR) in the form:

equation


where Ipeak is the peak current in the presence of anesthetic or nonimmobilizer normalized to the control peak current, IC50 is the concentration of anesthetic or nonimmobilizer that reduces the peak current to half of the control peak current, and n is the Hill coefficient.


   Results
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 Abstract
 Introduction
 Materials
 Methods
 Results
Discussion
 References
 
Nonhalogenated Alkane Anesthetics Inhibit Rat {alpha}4ß2 Neuronal nACh Receptors
Figure 1A demonstrates that cyclopropane significantly and reversibly inhibited currents elicited by 1 mM ACh and mediated by {alpha}4ß2 neuronal nACh receptors at a concentration equivalent to 0.7 MAC. Figure 1B plots the normalized current as a function of cyclopropane concentration and reveals that cyclopropane inhibited {alpha}4ß2 neuronal nACh receptors in a concentration-dependent manner. At the largest concentration studied (3 mM, 2.1 MAC), cyclopropane inhibited 93% ± 2% of the current. A fit of the data in this to Equation 1 yielded an IC50 of 570 ± 40 µM and a Hill coefficient of 1.2 ± 0.1.



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  		Figure 1. Nonhalogenated anesthetic alkanes inhibit rat {alpha}4ß2 neuronal nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes. A, Currents elicited by a 30-s pulse of 1 mM ACh in the absence of cyclopropane (control) or in the presence of 1000 µM cyclopropane. B, A cyclopropane concentration-response curve demonstrates that cyclopropane potently inhibits {alpha}4ß2 neuronal nACh receptors. The dashed line indicates the aqueous concentration of cyclopropane that corresponds to 1 minimum alveolar anesthetic concentration (MAC) in rats (1400 µM). The number above each data point indicates the number of oocytes used to obtain the mean. C, Currents elicited by a 30-s pulse of 1 mM ACh in the absence of butane (control) or in the presence of 300 µM butane. D, A butane concentration-response curve demonstrates that butane potently inhibits {alpha}4ß2 neuronal nACh receptors. The dashed line indicates the aqueous concentration of butane that corresponds to 1 MAC in rats (230 µM). The number above each data point indicates the number of oocytes used to obtain the mean, and the error bars indicate the standard deviation (*P < 0.05 versus control).

 
Butane also significantly and reversibly inhibited currents mediated by {alpha}4ß2 neuronal nACh receptors at a concentration equivalent to 1.3 MAC (Fig. 1C). A plot of the normalized current elicited by 1 mM acetylcholine as a function of butane concentration is shown in Figure 1D and demonstrates that butane inhibited {alpha}4ß2 neuronal nACh receptors in a con-centration-dependent manner. At the largest concentration studied (1 mM, 4.3 MAC), butane inhibited 89% ± 6% of the current. A fit of the data in Figure 1D to Equation 1 yielded an IC50 of 84 ± 7 µM and a Hill coefficient of 1.1 ± 0.1.

Perhalogenated Alkane Nonimmobilizers Inhibit Rat {alpha}4ß2 Neuronal nACh Receptors
The nonimmobilizer F6 also reversibly inhibited {alpha}4ß2 neuronal nACh receptors in a concentration-depen-dent manner (Fig. 2, A and B). At the largest concentration studied (200 µM, 9.0 MACpredicted), F6 inhibited 85% ± 2% of the current. At fit of a plot of the normalized peak current versus F6 concentration to Equation 1 yielded an IC50 of 29 ± 2 µM and a Hill coefficient of 0.92 ± 0.05. Similarly, the nonimmobilizer F8 reversibly inhibited {alpha}4ß2 neuronal nACh receptors in a concentration-dependent manner (Fig. 2, C and D) although at a near saturating aqueous concentration (30 µM, 2.7 MACpredicted), F8 inhibited only 60% ± 3% of the current, whereas cyclopropane, butane, and F6 inhibited 85%–93% of the current. Fitting the data in Figure 2D to Equation 1 yielded an IC50 of 13 ± 1 µM and a Hill coefficient of 0.68 ± 0.07.



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  		Figure 2. Perhalogenated nonimmobilizing alkanes inhibit rat {alpha}4ß2 neuronal nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes. A, Currents elicited by a 30-s pulse of 1 mM ACh in the absence of 1,2-dichlorohexafluorocyclobutane (F6) (control) or in the presence of 30 µM F6. B, The F6 concentration-response curve demonstrates that F6 inhibits {alpha}4ß2 neuronal nACh receptors. The dashed line indicates the aqueous concentration of F6 that corresponds to the predicted minimum alveolar anesthetic concentration (MAC) in rats (22 µM). The number above each data point indicates the number of oocytes used to obtain the mean. C, Currents elicited by a 30-s pulse of 1 mM ACh in the absence of butane (control) or in the presence of 10 µM 2,3-dichlorooctafluorobutane (F8). D, The F8 concentration-response curve demonstrates that F8 inhibits {alpha}4ß2 neuronal nACh receptors. The dashed line indicates the aqueous concentration of F8 that corresponds to the predicted MAC in rats (11 µM). The number above each data point indicates the number of oocytes used to obtain the mean, and the error bars indicate the standard deviation (*P < 0.05 versus control).

 
Perhalogenated Alkane Nonimmobilizers Inhibit Human {alpha}4ß2 Neuronal nACh Receptors
A previous study by Cardoso et al. (15) reported that nonimmobilizers fail to inhibit human {alpha}4ß2 neuronal nACh receptors at pharmacologically relevant concentrations. Because our data clearly demonstrated inhibition of rat {alpha}4ß2 neuronal nACh receptors within this concentration range, we considered the possibility that this discrepancy might reflect the different species used in each study; Cardoso et al. studied human receptors whereas we studied rat receptors. We tested this possibility by assessing the sensitivity of human {alpha}4ß2 neuronal nACh receptors to inhibition by F6. In this study, we elicited currents with 2 µM ACh rather than 1 mM ACh because human {alpha}4ß2 neuronal nACh receptors possess a 50% effective concentration for ACh that is approximately 2 orders of magnitude lower than rat {alpha}4ß2 neuronal nACh receptors (15). Figure 3 shows representative current traces mediated by human {alpha}4ß2 neuronal nACh receptors in the absence of F6 (control) and in the presence of F6 at the indicated concentrations and demonstrates that human {alpha}4ß2 neuronal nACh receptors are inhibited by F6 at pharmacologically relevant concentrations. Figure 4 plots the F6 concentration-response curve for inhibition of human {alpha}4ß2 neuronal nACh receptors. Fitting the data in Figure 4 to Equation 1 yielded an IC50 of 10.5 ± 0.5 µM and a Hill coefficient of 0.66 ± 0.03.



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  		Figure 3. The perhalogenated nonimmobilizing alkane 1,2-dichlorohexafluorocyclobutane (F6) inhibits human {alpha}4ß2 neuronal nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes. Currents were elicited by a 30-s pulse of 2 µM ACh in the absence of F6 (control) or upon exposure to the indicated concentrations of F6.

 


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  		Figure 4. The perhalogenated nonimmobilizing alkane 1,2-dichlorohexafluorocyclobutane (F6) inhibits human {alpha}4ß2 neuronal nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes with a 50% inhibitory concentration of 10.5 ± 0.5 µM and a Hill coefficient of 0.66 ± 0.03. The number above each data point indicates the number of oocytes used to obtain the mean, and the error bars indicate the standard deviation (*P < 0.05 versus control).

 

   Discussion
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 Abstract
 Introduction
 Materials
 Methods
 Results
 Discussion
References
 
Our studies demonstrate that the nonhalogenated anesthetic alkanes cyclopropane and butane and the perhalogenated nonimmobilizing alkanes F6 and F8 significantly inhibit {alpha}4ß2 neuronal nACh receptors at pharmacologically relevant concentrations. This observation strongly suggests that inhibition of {alpha}4ß2 neuronal nACh receptors does not account for the immobilizing activities of general anesthetics because, by definition, anesthetics and nonimmobilizers possess different abilities to inhibit movement. The receptor IC50s of these compounds correlate remarkably well with their oil/water partition coefficients without apparent regard to whether a compound is an anesthetic or nonimmobilizer, implying that if interactions with a single receptor binding site accounts for all of their inhibitory activities, then this site is likely to be hydrophobic in character and unable to distinguish between general anesthetics and nonimmobilizers (Fig. 5).



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  		Figure 5. A plot of the rat {alpha}4ß2 neuronal nACh receptor 50% inhibitory concentration (IC50) versus oil/water partition coefficient on a log-log scale demonstrates that isoflurane, cyclopropane, butane, 1,2-dichlorohexafluorocyclobutane (F6), and 2,3-dichloro-octafluorobutane (F8) inhibit rat {alpha}4ß2 neuronal nACh receptors with potencies that correlate with their hydrophobicities (3,17,18). We determined the IC50 for isoflurane to be 160 ± 20 µM and the Hill coefficient was 1.2 ± 0.2 (data not shown).

 
There have been two previous studies examining the effects of nonimmobilizers on neuronal nACh receptors. In a preliminary study, Matsuura et al. (16) reported that at pharmacologically relevant concentrations, F6 significantly inhibited both ganglionic-type nACh receptors in PC12 cells and central nervous system-type nACh receptors in acutely dissociated rat medial habenula neurons. They found that F8 also significantly inhibited nACh receptors in PC12 cells and tended to reduce currents mediated by nACh receptors in acutely dissociated rat medial habenula neurons (although the latter effect did not reach statistical significance). However, Cardoso et al. (15) reported no inhibition of {alpha}4ß2, {alpha}2ß4, or {alpha}3ß4 human neuronal nACh receptors by either F6 or F8. Our studies using human {alpha}4ß2 human neuronal nACh receptors indicate that species differences do not account for the apparent discrepancy between our results and those reported by Cardoso et al., but cannot explain the contradictory results. We have previously reported that F6 and F8 also inhibit the mouse muscle nACh receptor (14). In common with {alpha}4ß2 neuronal nACh receptors, mouse muscle nACh receptors are inhibited by these immobilizers in a concentration-dependent manner and with potencies that correlate with their oil solubilities.

The role that {alpha}4ß2 neuronal nACh receptors have in mediating the behavioral effects of general anesthetics is not clear. Flood et al. (13) demonstrated that isoflurane inhibits {alpha}4ß2 neuronal nACh receptors at the small concentrations that induce amnesia and suggested that anesthetic-induced impairment of learning and memory (amnesia) may result from inhibition of these receptors. Our data are consistent with this suggestion because the nonimmobilizer F6 also inhibits {alpha}4ß2 neuronal nACh receptors at concentrations that suppress learning in rats.


   Acknowledgments
 
This research was supported in part by Grant RO1-GM61927 from the National Institutes of General Medical Sciences.


   References
Top
 Abstract
 Introduction
 Materials
 Methods
 Results
 Discussion
 References
 

  1. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.[Medline]
  2. Raines DE, Claycom RJ, Scheller M, Forman SA. Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels. Anesthesiology 2001; 95: 470–7.[Web of Science][Medline]
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  6. Eger EI II, Koblin DD, Sonner J, et al. Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. Anesth Analg 1999; 88: 884–92.[Abstract/Free Full Text]
  7. Role LW. Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels. Curr Opin Neurobiol 1992; 2: 254–62.[Medline]
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  12. Violet JM, Downie DL, Nakisa RC, et al. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology 1997; 86: 866–74.[Web of Science][Medline]
  13. Flood P, Ramirez LJ, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected [see comments]. Anesthesiology 1997; 86: 859–65.[Web of Science][Medline]
  14. Forman SA, Raines DE. Nonanesthetic volatile drugs obey the Meyer-Overton correlation in two molecular protein site models. Anesthesiology 1998; 88: 1535–48.[Web of Science][Medline]
  15. Cardoso RA, Yamakura T, Brozowski SJ, et al. Human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes predict efficacy of halogenated compounds that disobey the Meyer-Overton rule. Anesthesiology 1999; 91: 1370–7.[Web of Science][Medline]
  16. Matsuura T, Andoh T, Kamiya Y, et al. Inhibitory effects of isoflurane and nonimmobilizing halogenated compounds on neuronal nicotinic receptors. American Society of Anesthesiologists annual meeting. San Francisco: Lippincott Williams & Wilkins, 2000: A-763.
  17. Fang Z, Ionescu P, Chortkoff BS, et al. Anesthetic potencies of n-alkanols: results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics. Anesth Analg 1997; 84: 1042–8.[Abstract]
  18. Firestone LL, Miller JC, Miller KW. Table of physical and pharmacological properties of anesthetics. In: Roth SH, Miller KW, eds. Molecular and cellular mechanisms of anesthetics. New York: Plenum Press, 1986: 455–70.
Accepted for publication February 5, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press