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Anesth Analg 2000;91:741-748
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Nonstereoselective Inhibition of Neuronal Nicotinic Acetylcholine Receptors by Ketamine Isomers

Toshio Sasaki, MD, Tomio Andoh, MD, PhD, Itaru Watanabe, MD, Yoshinori Kamiya, MD, Hideki Itoh, MD, Tomoko Higashi, MD, and Takayuki Matsuura, MD

Department of Anesthesiology, Yokohama City University School of Medicine, Yokohama, Japan

Address correspondence and reprint requests to T. Andoh, MD, PhD, Department of Anesthesiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Address e-mail to tandoh{at}med.yokohama-cu.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We have found that racemic ketamine strongly inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAchRs) in PC12 cells, a rat pheochromocytoma cell line. Ketamine stereoisomers have different potencies for the anesthetic action, with the S-enantiomer being about 3 times as potent as the R-enantiomer. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAchRs contribute to their anesthetic effect. We compared potencies of ketamine enantiomers for neuronal nAchR inhibition with those for the anesthetic action. S(+) and R(-) ketamine inhibited the nicotine-induced whole-cell current in a dose-dependent manner at the membrane potential of -60 mV. They accelerated the current decay, resulting in the larger effects on the nondesensitized current than on the peak current. There was no significant difference in the concentrations for 50% inhibition between the stereoisomers. The ketamine isomers exerted the same effects on single-channel properties estimated from analysis of the nicotine-induced current noise. These results indicate that the inhibitory action of ketamine isomers on neuronal nAchRs is not stereoselective. Although our findings do not deny possible involvement of these receptors in ketamine anesthesia, they suggest that inhibition of neuronal nAchRs is not primarily responsible for the anesthetic action of this anesthetic.

Implications: We found that inhibition of neuronal nicotinic acetylcholine receptors by ketamine is not stereoselective in PC12 cells. The result suggests that this effect does not directly correlate with the anesthetic action of ketamine.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ketamine’s primary site of action is probably N-methy-D-aspartate (NMDA) receptors (1,2). We have been investigating the effects of anesthetics on neuronal nicotinic acetylcholine receptors (nAchRs) (3) and have found that racemic ketamine strongly inhibits the neuronal nAchR-mediated current in PC12 cells, a rat pheochromocytoma cell line (4). Neuronal nAchRs are very sensitive to a number of different anesthetics, such as barbiturates and volatile anesthetics (3,5,6). The receptors are widely expressed in the central nervous system (CNS) and the autonomic nervous system (7). Although the role of neuronal nAchRs in the CNS is not clear, some investigations suggest that these receptors are important in memory and cognitive function (8–10). Therefore, it is possible that neuronal nAChRs are responsible for particular aspects of the anesthetic state, such as amnesia and impairment of learning. The inhibition of neuronal nAchRs by ketamine is significant at the concentrations well below those seen during anesthesia (4), which suggests that the inhibition might be associated with psychological disturbances after ketamine anesthesia administration.

Ketamine stereoisomers have different potencies for the anesthetic action in humans, with the S-enantiomer being about 3 times as potent as the R-enantiomer (11,12). In rats, ketamine isomers similarly exert stereoselective potency differences in producing hypnosis, i.e., the 50% effective dose of S(+) isomer for depression of the righting reflex is 3 times lower than that for R(-) isomer in rats (13). The enantiomers differentially block NMDA receptor currents with S(+) ketamine being about twice as potent as R(-) ketamine (14). This finding supports relevance of NMDA receptors in the anesthetic action of ketamine, because it is likely that the primarily responsible sites for ketamine’s anesthetic action have stereoselective sensitivity to this anesthetic. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAChRs contribute to the anesthetic effect of this anesthetic by comparing potencies of ketamine enantiomers for neuronal nAchR inhibition with those for the anesthetic action. We compared the effects of the optical isomers of ketamine on the neuronal nAchR-mediated current in PC12 cells at clinically relevant concentrations using whole-cell voltage clamp recording. Further, we compared the effects of the isomers on single-channel variables estimated with noise analysis.

Neuronal nAchRs expressed in PC12 cells are likely to be different from their counterparts in the CNS for subunit compositions and pharmacological properties (7). Although PC12 cells contain mRNA of {alpha}3, {alpha}5, {alpha}7, ß2, ß3, and ß4 subunits and {alpha}3ß4-containing receptors are thought to be predominant in this cell line (15), the central-type receptors consist of multiple subtypes formed with {alpha}2–9 and ß2–4 subunits and {alpha}4ß2 receptors represent a major part of nicotine binding sites in the brain (7). ß4-containing receptors, such as {alpha}3ß4 and {alpha}4ß4 receptors, are also expressed in some regions of the CNS (16). Ketamine inhibits the current most likely through an interaction with the phencyclidine (PCP) binding site located in the pore forming M2 segment of the channel (17), because ketamine is structurally related to PCP and blocks PCP binding to nAchRs of Torpedo membranes (18). This region is well conserved among the different subunits of nAchRs (19). Therefore, we assumed that ketamine similarly inhibits the current through ganglionic type and central type nAchRs by acting on the well conserved domain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Cell Culture and Electrophysiological Methods
PC12 cells were cultured as previously described (3). Cells were not treated with nerve growth factors. For the experiment, cells were plated on collagen and poly-1-lysine-coated cover slips and used after an additional 4 days in culture. Membrane currents were recorded by using the whole-cell voltage-clamp method (20) under the conditions described previously (4). Cells on the coverslips were placed in a recording bath with an approximate volume of 1.5 mL and were continuously perfused at the rate of 1–2 mL/min with a standard external solution containing (in mM): NaCl 140, KCl 5.4, CaCl2 1.8, MgCl2 1.0, N-2-hydroxy-ethylpiperazine-N'-2-ethanesulphonic acid (HEPES) 10, glucose 11.1 (pH was adjusted to 7.4 with NaOH). Heat-polished patch pipettes had a tip resistance of 2–7M{Omega} when filled with an intracellular solution containing (in mM): CsCl 150, HEPES 10, ethylene glycol-bis-(ß-aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA) 5, adenosine-5'-triphosphate Mg salt (ATP-Mg) 2 (pH 7.3 with CsOH). Cells were voltage-clamped at -60 mV with a patch-clamp amplifier (CEZ2400, Nihon Koden, Tokyo, Japan). Whole-cell currents were filtered at 0.2 kHz with a Bessel filter and digitized at 1 kHz. Data were stored and analyzed on a microcomputer by using pClamp software and Axograph (Axon Instruments, Foster City, CA.). All experiments were performed at room temperature (22–25°C).

Drug Application
Nicotine in the external solution was applied to cells by a rapid application technique previously described (3). This method enabled the complete exchange of the external solution surrounding the cell at approximately 100 ms, as estimated by recording the liquid junction current produced at an open-patch pipette. Single PC12 cells were exposed to 3 to 1000 µM of nicotine to obtain a dose-response relationship for nicotine. To compare the effects of ketamine stereoisomers on the nicotine-induced whole-cell current, nicotine 30 µM, with or without ketamine isomers, was applied for 5 s, and each application was separated by 5 min. For preincubation with the anesthetics, the external solutions containing the drugs were perfused at the rate of 5 mL/min for 5 min before rapid application. Cells were perfused with the plain external solution at the same rate for 5 min to washout the drugs from the bath after the measurement.

Data Analysis
We measured the peak current and the nondesensitized current, which was defined as the average of the proceeding 50 points at 4 s during agonist application. Because nicotine-elicited currents declined with each application of the agonist, the response in the presence of ketamine isomers was compared with the average of the elicited current before and after ketamine isomer application. This procedure was rationalized by the finding that the second response was almost the same as the average of the first and third responses when nicotine was applied successively three times with an interval of 5 min. To avoid bias from cell-to-cell differences in the sensitivity to ketamine, we compared the effects of ketamine isomers in the same cells that were exposed to the isomers in a random sequence.

Desensitization was evaluated by calculating the percentage decay of the current (% current decay) defined by the following equation (21): Go


Noise Analysis
We performed noise analysis to study mechanisms of actions of ketamine isomers. For analysis of whole-cell current noise, PC12 cells were exposed to nicotine 10 µM with or without ketamine enantiomers 10 µM for at least 15 s under voltage clamp at -60 mV. Ketamine isomers were applied after 5 min preincubation. The signals were low-pass filtered at 1 kHz through an 8-pole Butterworth filter (Model 900; Frequency Devices, Haverhill, MA.) and digitized at 5 kHz. The data were divided into consecutive 0.41-s blocks before calculation of the spectral density. The mean power spectrum was calculated by averaging at least 32 of the spectra obtained from the 0.41-s time blocks. To obtain the noise spectrum caused by the application of nicotine, the spectrum obtained before application of the agonist was subtracted from that obtained during nicotine application. Either single or double Lorentzian curves were fitted to the power spectrum by minimizing the squares of the deviations between the experimental points and calculated functions. All data points were equally weighted, and Levenberg-Marquaedt iterative curve fitting algorithm was used (22). The Lorentzian function is defined by the equation: Go


where S(f) is spectral density, S(0) is the low frequency asymptote, f is frequency, and fc stands for the corner frequency of the power spectrum. The single-channel open time constant ({tau}) was estimated by using the following equation: Go


The average unitary conductance ({gamma}) was derived from variance of current noise by using the following equations (23): Go


where {varsigma} = variance of current noise, {triangleup}I = the agonist-induced mean current change, VD = driving force caused by the difference between the holding potential and the equilibrium potential.

Drugs
(-)-Nicotine was purchased from Wako (Osaka, Japan), and ATP-Mg was from Sigma (St. Louis, MO). Ketamine isomers were supplied by Park-Davis GmbH (Berlin, Germany).

The data were expressed as mean ± SEM. A paired t-test was performed to analyze differences between S(+) and R(-) ketamine isomers and to compare the results in the absence and presence of ketamine isomers. Comparison among the values at different doses of ketamine was made by using analysis of variance followed by the Scheffé test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Nicotine elicited inward currents, which decayed rapidly during nicotine application as a result of desensitization, at the membrane potential of -60 mV. The induced current exhibited the characteristics of the neuronal nAchR-mediated current, i.e., it was sensitive to hexamethonium and showed a strong inward rectification in the current-voltage relationship (3). The dose-response relationship for the peak current showed that the concentration of nicotine required for half maximal activation was 11.2 µM and that the peak response was saturated at the doses equal to or more than 100 µM of nicotine (Fig. 1). For the nondesensitized current, the response increased up to 30 µM of nicotine, and nicotine 10 µM produced approximately a half maximal response. The nondesensitized current decreased at the doses more than 30 µM as a result of augmented desensitization (data not shown). We used nicotine 30 µM as the agonist in the following experiments, because it is a saturating dose for the nondesensitized response and the peak response was near saturated at 30 µM. The peak amplitudes varied greatly from cell to cell, from 40 to 700 pA at nicotine 30 µM.



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  		Figure 1. Dose-response relationship for activation of nicotinic acetylcholine receptors. Single PC12 cells were exposed to 3 to 1000 µM of nicotine in a random order, and whole-cell currents were recorded at the membrane potential of -60 mV. Nicotine 30 µM and two or three other concentrations were applied to each cell with an interval of 5 min. The peak currents were normalized to the responses at nicotine 30 µM measured in the corresponding cells and then plotted against the agonist concentration (n = 3 to 6 for each dose). The dose-response curve was described by a Hill equation. The concentration of nicotine required for half maximal activation was 11.2 ± 2.1 µM, and the Hill coefficient was 1.4 ± 0.3.

 
Both S(+) and R(-) ketamine, at 0.3–10 µM, inhibited the inward current elicited by nicotine 30 µM reversibly in a dose-dependent manner (Fig. 2, A and B). The stereoisomers accelerated the current decay almost equally, resulting in similar increases in % current decay (Table 1). The acceleration of the current decay resulted in the greater inhibition of the nondesensitized current than that of the peak current. The concentrations for 50% inhibition (IC50) for the peak current were 5.2 ± 0.5 µM and 5.4 ± 0.5 µM for S(+) and R(-) ketamine. IC50 values for the nondesensitized current were 1.1 ± 0.2 µM and 1.7 ± 0.4 µM for S(+) and R(-) ketamine. There were no significant differences in IC50 values between the stereoisomers (Fig. 2, C and D).



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  		Figure 2. A and B, Inhibition by ketamine isomers of the whole-cell current evoked by nicotine 30 µM in PC12 cells. Cells were held at -60 mV. Nicotine 30 µM was applied during the period indicated by the thin horizontal bars. S(+) ketamine (A) or R(-) ketamine (B) 3 µM was coapplied with nicotine after 5-min preincubation as indicated by the thick bars. The stereoisomers inhibited the nicotine-induced current and accelerated the current decay in a similar manner. C and D, The concentration-inhibition curves for S(+) and R(-) ketamine on the nicotine-induced whole-cell current. The peak (C) and nondesensitized (D) currents in the presence of ketamine were normalized to the average of the control currents before and after ketamine and plotted against the concentration of ketamine (n = 6 or 7 for each dose). Data points were fitted to the empirical Hill equation by a least-squares fit: I = 1 - Cn/(Cn + IC50n), where I = relative current, C = concentration of ketamine, n = the Hill coefficient, IC50 = the ketamine concentration for 50% inhibition. IC50 values and Hill coefficients for the peak current inhibition were 5.2 ± 0.5 µM and 1.3 ± 0.1 for S(+) ketamine and 5.4 ± 0.5 µM and 1.2 ± 0.1 for R(-) ketamine. IC50 values and Hill coefficients for the nondesensitized current inhibition were 1.1 ± 0.2 µM and 0.9 ± 0.1 for S(+) ketamine and 1.7 ± 0.4 µM and 1.1 ± 0.2 for R(-) ketamine. There was no significant difference in these values between the stereoisomers.

 

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  		Table 1. Percent Current Decay With or Without Ketamine Isomers
 
To see if there was any interaction between the isomers, we compared the effects of the S(+) isomer 3 µM with those of the mixture of 3 µM of the S(+) and R(-) isomers, which yields the solution containing 1.5 µM of S(+) and R(-) isomers at the final concentration. Relative peak and nondesensitized currents were 0.53 ± 0.05 and 0.27 ± 0.07 in the presence of the S(+) isomer and 0.53 ± 0.09 and 0.28 ± 0.11 in the presence of the mixture (n = 4 for each condition). There was no significant difference between the magnitudes of inhibition by the S(+) isomer and the mixture.

In current noise recordings, nicotine 10 µM induced current responses that exhibited little desensitization and produced large increases in current fluctuations (noise) (Fig. 3). Coapplication of ketamine isomers with nicotine induced smaller responses with the reduced current noise. Analysis showed that current noise induced by nicotine 10 µM gave power spectra that were best fitted by two Lorentzian functions (Fig. 4). The enantiomers reduced the low frequency asymptotes (S0) and increased the corner frequencies of the first and second components in the power spectrum (Fig. 4 and Table 2). The similar changes in fitted power spectra by ketamine isomers were obtained in six other experiments. The single-channel open time derived from the Lorentzian curve fitting was shortened by the isomers for both the first and second components (Table 2). Unitary conductance estimated from variance of current noise did not significantly change in the presence of ketamine isomers, compared with nicotine alone (Table 2). There was no significant difference in these single-channel properties inferred from noise analysis between the R(-) and S(+) stereoisomers.



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  		Figure 3. The representative current traces used for noise analysis in the absence and presence of ketamine isomers. Nicotine 10 µM was applied during the period indicated by the light horizontal bars. S(+) ketamine (A) or R(-) ketamine (B) 10 µM was coapplied with nicotine after 5-min preincubation as indicated by the thick bars. Coapplication of the stereoisomers with nicotine produced smaller responses with the reduced amplitudes of current fluctuations, compared with nicotine alone. The long vertical lines at the beginning of nicotine application are the artifacts caused by the closure of the electromagnetic valve.

 


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  		Figure 4. Changes in the power spectra of the nicotine-induced current noise by S(+) (A) and R(-) ketamine (B). The noise spectra were fitted by two Lorentzian functions. Ketamine isomers reduced the low frequency asymptotes and increased the corner frequencies of both the first and second Lorentzian at 10 µM. fc = the corner frequency.

 

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  		Table 2. Changes in Power Spectra of Nicotine-Induced Current Noise and Single-Channel Variables Inferred from Noise Analysis
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of the present study demonstrate that ketamine enantiomers nonstereoselectively inhibited the neuronal nAchR-mediated current in PC12 cells. Both S(+) and R(-) ketamine similarly depressed the nicotine-induced whole-cell current and augmented the current decay at clinically relevant concentrations, which are estimated to be 4–7 µM in free plasma concentration (24,25). Changes in the nicotine-induced current noise were also indistinguishable between ketamine isomers. Both isomers reduced the single-channel open time derived from noise analysis comparably without changing unitary conductance. Although the lack of stereoselectivity does not exclude the possible involvement of neuronal nAchRs in ketamine anesthesia, it suggests that the inhibitory effects on neuronal nAchRs are not primarily responsible for the anesthetic action of ketamine.

Our finding of nonstereoselective inhibition of neuronal nAchRs by ketamine is consistent with the earlier studies investigating effects of PCP-like compounds on nAchRs (26,27). The stereoisomers of PCP-like drugs, dexoxadrol, levoxadrol, and (+)/(-)1-(1-phenyl cyclohexyl)-3-methyl piperidine have no stereospecificity for inhibition of the nicotine-induced catecholamine secretion in adrenal chromaffin cells (26). MK801 blocks human {alpha}7 nAchR expressed in Xenopus oocytes without stereoselectivity (27). These compounds inhibit NMDA receptors stereoselectively (28,29). Therefore, it seems that blocking actions of these PCP-like compounds, including ketamine and MK801, are stereoselective for NMDA receptors but nonstereoselective for nAchRs.

We used noise analysis to estimate single-channel properties, because channel activities do not last long enough for kinetic analysis in excised patches. Power spectra of the nicotine-induce current noise were fitted to two Lorentian functions, suggesting that two distinct open states exist. We found that ketamine isomers reduced the open time estimated from analysis of both components of power spectra. This finding is consistent with the acceleration of current decay observed in whole-cell recordings and with earlier investigations demonstrating that ketamine decreases the open time of single-channel currents in muscle type nAchRs (30,31). Reduction of the open time accords with open channel block as a mechanism of inhibition, but will not exclude other mechanisms such as inhibition of closed channels, which has been also addressed for ketamine’s actions on nAchRs (32). The results of noise analysis also provide evidence supporting nonstereoselectivity of ketamine’s inhibition for mechanisms of inhibition and single-channel behavior.

Ketamine inhibits the response mediated through muscarinic acetylcholine receptors (33). The muscarinic inhibitory action of ketamine isomers is not stereoselective, but the isomers exhibit a synergistic interaction (34). The mixture of ketamine enantiomers has a significantly lower IC50 for suppression of muscarinic responses than each enantiomer. We compared the inhibitory effects of the mixture of ketamine isomers and the S(+) isomer on the nAchR-mediated current and found no difference in the magnitudes of depression. The result suggests that there is no synergistic or antagonistic interaction between the stereoisomers in the inhibition of neuronal nAchRs.

The S(+) isomer is three- to fourfold more potent compared with the R(-) isomer as an anesthetic and analgesic (11,12). However, it is not completely clear if ketamine isomers exhibit the same stereospecificity in producing the impairment of psychomotor function after anesthesia. A clinical study showed that deleterious psychological emergence reactions are several times more common after anesthesia with the R(-) isomer than the S(+) isomer in surgical patients receiving almost equianesthetic doses of ketamine isomers (11). One possible explanation for this finding may be that the isomers are roughly equipotent in producing psychomotor disturbance, but the R(-) isomer caused more deleterious psychological emergence reactions because the dose of the R(-) isomer was 3 times larger than the S(+) isomer. This interpretation might favor nonstereoselective actions of ketamine isomers on psychological states. In contrast to this, a controlled study using healthy volunteers showed that S(+) ketamine is 3 to 5 times more potent than R(-) ketamine for impairing psychomotor functions during recovery from ketamine anesthesia without surgery (12). An animal experiment also reported that ketamine isomers stereoselectively affect maze performance in the mouse (35). Therefore, it is likely that surgery and postoperative pain influenced the incidence of deleterious psychological emergence reactions in surgical patients. The R(-) isomer caused more deleterious psychological emergence reactions than the S(+) isomer probably because postoperative pain was more common after anesthesia with R(-) ketamine (11). Taken together, ketamine isomers have stereoselective actions in producing anesthesia and impairing psychomotor functions. The primarily responsible site(s) for these actions should exhibit stereoselective sensitivity to ketamine isomers. Therefore, assuming that ketamine isomers similarly exhibit nonstereoselective inhibition of human central nicotinic receptors, it is unlikely that inhibition of neuronal nAchRs is primarily responsible for these clinical effects. However, because neuronal nAchRs are very sensitive to clinically relevant concentrations of ketamine, it is possible that inhibition of neuronal nAchRs by ketamine is related to some aspects of the anesthetized and postanesthetized states.

Central type neuronal nAchRs are heterogeneous and have subunit compositions and pharmacological profiles different from those of ganglion type receptors (19). Ketamine and a closely related compound, MK801, strongly inhibit the current or the response mediated through nAchRs of muscle, ganglionic, and central types (4,32,36,37). The inhibitions by MK801 are reportedly noncompetitive for all three types, suggesting a common mechanism of blocking actions on these receptors (37). However, we cannot automatically extend the results of this study, i.e., nonstereoselective inhibition by ketamine, to all subtypes of nAchRs in the CNS.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 30, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press