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NEUROPHARMACOLOGY
Department of Anesthesia and Critical Care, Massachusetts General Hospital, and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts (K.S., P.A.D., D.E.R.); and Neuroscience Program, University of California at San Diego, San Diego, California (R.J.S.)
Received for publication
June 6, 2005
Accepted
August 3, 2005.
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Abstract |
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). Until fairly recently, only one subunit (5-HT3A) of the 5-HT3 receptor had been cloned and characterized (Maricq et al., 1991), and homomeric 5-HT3A receptors were the only subtype known. However, a second subunit (5-HT3B) has been identified and cloned, and although homomeric receptors cannot be formed with 5-HT3B subunits, they can be combined with 5-HT3A subunits to form heteromeric 5-HT3AB receptors (Davies et al., 1999). These heteromeric receptors possess functional properties that are distinct from those of homomeric 5-HT3A receptors, and their 5-HT-evoked responses are more similar to those observed in neuronal preparations (Davies et al., 1999; Dubin et al., 1999).
5-HT3 receptors are thought to play important roles in regulating a variety of organ systems, in particular the cardiovascular and nervous systems. For example, there is evidence that 5-HT3 receptors in the nucleus tractus solitarius are important modulators of the baroreflex (Comet et al., 2005), carotid chemoreflex (Sevoz et al., 1997), and the Bezold-Jarisch reflex (Pires et al., 1998). Presynaptic 5-HT3 receptors also modulate GABA release (Koyama et al., 2000, Turner et al., 2004), an effect that may play a role in the mechanism of action of inhaled anesthetics. There is also substantial evidence that 5-HT3 receptors are involved in nociception (Zeitz et al., 2002). In addition, 5-HT3 receptors are important modulators of emesis, as evidenced by the efficacy of 5-HT3 receptor antagonists in the treatment of postoperative nausea and vomiting, which has been strongly linked to the use of halogenated volatile anesthetics (Apfel et al., 2002). Thus, modulation of 5-HT3 receptors may contribute to the mechanism of action as well as some of the undesirable side effects of volatile anesthetics.
At clinically relevant concentrations, physically small, halogenated volatile anesthetics such as halothane and chloroform significantly potentiate submaximal 5-HT3A receptor-mediated current responses evoked by 5-HT (Stevens et al., 2005b). However, heteromeric 5-HT3AB receptors have been found to be generally much less sensitive to such anesthetic-induced potentiation of current responses than homomeric 5-HT3A receptors (Stevens et al., 2005a). Studies using a range of 5-HT concentrations demonstrate that for 5-HT3A receptors, the presence of small, halogenated anesthetics significantly reduces the EC50 for 5-HT without increasing the maximal response to 5-HT (Stevens et al., 2005b). However, this anesthetic-induced reduction in agonist EC50 is greatly attenuated when 5-HT3B subunits are incorporated to produce heteromeric 5-HT3AB receptors (Stevens et al., 2005a). The present study sought to define the underlying mechanism accounting for the difference in anesthetic-induced sensitivity to agonist between the two 5-HT3 receptor subtypes. We used dopamine (DA), a highly inefficacious agonist for 5-HT3 receptors, to determine whether the difference in sensitivity of 5-HT3A and 5-HT3AB receptors to the potentiating effects of small, halogenated anesthetics is due to differential modulation of agonist affinity, channel gating, or both.
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Materials and Methods |
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). The Massachusetts General Hospital Animal Care Committee approved all animal housing and surgical procedures. cDNA encoding the 5-HT3A and 5-HT3AB subunits (kindly provided by E. Kirkness, The Institute for Genomic Research, Rockville, MD) were transcribed into messenger RNA using the mMESSAGE mMACHINE high yield capped RNA transcription kit (Ambion, Austin, TX). After treatment with collagenase IA for 1 h, stage V and VI oocytes were manually defolliculated and injected with 25 to 50 nl of RNA encoding the 5-HT3A subunit to express homomeric 5-HT3A receptors, or a mixture of RNA encoding the 5-HT3A and 5-HT3B subunits (in a ratio of 1:2:1 by volume for 5-HT3A subunit/5-HT3B subunit/water) to express heteromeric 5-HT3AB receptors. Oocytes were kept at 18°C in ND-96 incubation solution (containing 96 mM NaCl, 2 mM KCl, 10 mM HEPES, 1.8 mM CaCl2, 1.0 mM MgCl2, 5 units/ml penicillin, and 5 µg/ml streptomycin, pH adjusted to 7.5 with NaOH) for 3 to 7 days before electrophysiological experimentation.
Electrophysiological Recordings. Electrophysiological recordings were performed using the whole-oocyte two-electrode voltage-clamp technique at room temperature (22-24°C). Oocytes were held at a cross-membrane potential of -50 mV using a GeneClamp 500B amplifier (Molecular Devices, Inc., Sunnyvale, CA). Capillary glass electrodes filled with 3 M KCl and possessing open tip resistances less than 5 M
were used to impale oocytes. During experimentation, oocytes were continuously superfused at a rate of 5 ml/min with ND-96 buffer (containing 96 mM NaCl, 2 mM KCl, 10 mM HEPES, 1 mM CaCl2, 0.8 mM MgCl2, pH adjusted to 7.5 with NaOH) in a 0.04-ml recording chamber using a gas-tight closed syringe superfusion system, producing an estimated solution exchange time of 0.5 to 1 s. Control of buffer perfusion was accomplished using a six-channel valve controller (Warner Instruments, Hamden, CT) interfaced with a Digidata 1322A data acquisition system (Molecular Devices, Inc.) and driven by a Dell personal computer (Dell, Round Rock, TX). The perfusion apparatus was constructed with gas-tight glass syringes and Teflon tubing to minimize absorptive and evaporative loss of anesthetic drugs. In parallel experiments, gas chromatographic analysis of solutions entering the oocyte chamber indicated that such loss was less than 15%. Current responses were recorded using Clampex 9.0 software (Molecular Devices, Inc.) and filtered using a Bessel (eight-pole) low-pass filter with a -3-dB cut-off at 1.56 Hz (Clampfit 9.0; Molecular Devices, Inc.) before analysis.
Preparation of Volatile Anesthetic and DA Solutions. Volatile anesthetic solutions were prepared by adding an excess of anesthetic agent to a sealed glass bottle containing recording buffer solution and stirring with a Teflon-coated stir bar overnight. The resulting saturated anesthetic solution of known concentration was subsequently diluted with buffer solution using a gas-tight syringe to obtain the final desired anesthetic concentration. The anesthetizing concentrations of halogenated volatile anesthetics were defined as the aqueous concentrations corresponding to 1 MAC in humans, calculated using the aqueous/gas partition coefficient at 37° (Franks and Lieb, 1993).
Because DA oxidizes and precipitates in aqueous solution over time, buffer solutions were deoxygenated by stirring under vacuum for at least 30 min and subsequently put on ice before adding DA. DA-containing solutions were kept on ice in the dark until immediately before experimentation, at which time the solution was brought to room temperature using a water bath. Using these techniques, no visible DA precipitation was observed over the course of experimentation.
Experiments to Establish 5-HT and DA Concentration-Response Relationships. To establish 5-HT and DA concentration-response relationships, a control experiment was first performed by perfusing the oocyte for 15 s with buffer solution containing a concentration of 5-HT known to elicit maximal current (100 µM 5-HT for 5-HT3A receptors and 300 µM 5-HT for 5-HT3AB receptors). After a recovery period of 5 min, the test experiment was performed by perfusing the cell for 15 to 60 s with buffer solution containing either 5-HT or DA at the desired concentration. After another recovery period of 3 to 5 min, a second control experiment was performed using a concentration of 5-HT that elicits maximal current. Peak current responses were recorded, and the current response from the test experiment was normalized to the average of the two maximal 5-HT-evoked controls performed immediately before and after each test experiment.
To establish DA concentration-response relationships in the presence of anesthetics, the cell was allowed to recover for 5 min after the control experiment using a concentration of 5-HT that elicits maximal current, and the test experiment was performed by first perfusing the oocyte with anesthetic solution alone for 30 s, and then immediately switching to a solution containing both anesthetic and DA for 75 s. A final control experiment was performed after a 3- to 5-min recovery period using a concentration of 5-HT that elicits maximal current. Peak current responses were recorded, and the current response from the test experiment was normalized to the average of the two maximal 5-HT-evoked controls performed immediately before and after each test experiment. All experiments using anesthetics had matched controls (without anesthetic) using the same oocytes, to account for cell-to-cell variability in current responses and agonist EC50.
Experiments to Establish Anesthetic Concentration-Response Relationships. To establish anesthetic concentration-response relationships in the presence of receptor-saturating concentrations of DA, a control experiment was first performed by perfusing the oocyte for 60 s with buffer solution containing a concentration of DA known to elicit maximal current (1 mM DA for 5-HT3A receptors and 2 mM DA for 5-HT3AB receptors). After a 3-min recovery period, the test experiment was performed by perfusing the cell with anesthetic solution alone for 30 s and then immediately switching to a solution containing both anesthetic and DA for 75 s. After another 3-min recovery period, a second control experiment was performed using a concentration of DA known to elicit maximal current. Peak current responses were recorded, and the current response from the test experiment was normalized to the average of the two maximal DA-evoked controls performed immediately before and after each test experiment.
Statistical Analysis. Normalized data were plotted as mean ± standard deviation. 5-HT and DA concentration-response data were fitted to a Hill equation in the form I = Imax/[1 + (EC50/[agonist])n], where I is the peak current evoked by agonist, Imax is the maximum current evoked by high agonist concentrations, EC50 is the concentration of agonist that elicits 50% of the maximal response, and n is the Hill coefficient. Data were analyzed using Igor Pro 4.01 software (Wavemetrics, Lake Oswego, OR). Statistical analyses were performed using Prism 4.0 software (GraphPad Software Inc., San Diego, CA).
Drugs and Chemicals. 5-HT, DA, ethyl 3-aminobenzoate methanesulfonate salt (tricaine), and collagenase IA were purchased from Sigma-Aldrich (St. Louis, MO). Isoflurane, halothane, and chloroform were purchased from Baxter (Deerfield, IL), Halocarbon Laboratories (River Edge, NJ), and Fisher Scientific (Fair Lawn, NJ), respectively. All other chemicals were reagent grade.
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Results |
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The potentiation of maximal DA-evoked currents by chloroform, halothane, and isoflurane over a range of clinically relevant concentrations (0.25-2 MAC) is shown in Fig. 3. For both receptor subtypes, anesthetic-induced potentiation of DA-evoked current responses increased in an anesthetic concentration-dependent manner. For 5-HT3A receptors, 2 MAC chloroform yielded the greatest current potentiation (745 ± 97%), followed by halothane (507 ± 128%) and isoflurane (60 ± 14%). The same was true for 5-HT3AB receptors, although the magnitude of the current potentiation for all three anesthetics was substantially less than that observed for 5-HT3A receptors (at 2 MAC, chloroform, halothane, and isoflurane elicited increases of 107 ± 5, 87 ± 5, and 8 ± 4%, respectively). Using a paired two-tailed t test, all anesthetic-induced increases in DA-evoked currents were found to be statistically significant (p < 0.05) for 5-HT3A receptors, with the single exception of isoflurane at 0.25 MAC. For 5-HT3AB receptors, all anesthetic-induced increases in DA-evoked currents were found to be statistically significant (p < 0.05), except for halothane at 0.25 MAC and isoflurane at 0.25 MAC, 0.5 MAC, and 2 MAC.
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In contrast to the effects observed for 5-HT3A receptors, 2 MAC chloroform and halothane had relatively minor effects on the DA concentration-response relationship for 5-HT3AB receptors, increasing Imax by 125 and 92%, respectively. 2 MAC isoflurane had no effect on Imax for 5-HT3AB receptors (3.3 ± 0.2% of maximal 5-HT-evoked response in the absence of isoflurane versus 3.4 ± 0.1% of maximal 5-HT-evoked response in the presence of isoflurane). None of the three test anesthetics altered the EC50 of the DA concentration-response relationship to a significant degree for either receptor subtype.
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Discussion |
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). Thus, a highly efficacious agonist cannot be used to determine the kinetic step upon which an anesthetic acts. However, when using a highly inefficacious agonist such as DA, effects on each step become readily distinguishable, because enhancement of channel gating produces an increase in current responses evoked by high agonist concentrations, whereas an increase in agonist affinity does not.
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The results of this study indicate that at clinically relevant concentrations, chloroform, halothane, and isoflurane increase the agonist sensitivity of homomeric 5-HT3A receptors by enhancing channel gating. Our previous work with 5-HT3A receptors using a concentration of 5-HT that elicits 10% of the maximal obtainable current (EC10) showed that at 2 MAC, chloroform induced the greatest amount of current enhancement (215%), followed by halothane (92%) and isoflurane (33%) (Stevens et al., 2005b). Consistent with those results, the present study using receptor-saturating concentrations of DA as agonist found that at 2 MAC, chloroform induced the greatest amount of channel gating enhancement, followed by halothane and then isoflurane.
Similarly, our previous work with 5-HT3AB receptors using a submaximal (EC10) concentration of 5-HT showed that at 2 MAC, chloroform (121%) induced more current enhancement than halothane (43%), whereas isoflurane induced no appreciable current enhancement (Stevens et al., 2005a). Consistent with those results, the present study using receptor-saturating concentrations of DA as agonist found that chloroform induced more channel gating enhancement than halothane, whereas isoflurane did not enhance gating. For both receptor subtypes, none of the three test anesthetics significantly altered the agonist EC50 for DA, indicating that these anesthetics do not affect agonist binding affinity to 5-HT3 receptors.
The present work also reveals that compared with homomeric 5-HT3A receptors, heteromeric 5-HT3AB receptors have markedly attenuated sensitivity to anesthetic-induced channel gating enhancement. This explains previous results demonstrating that anesthetics produce relatively little reduction in the 5-HT3AB receptor's EC50 for 5-HT in comparison with that seen with the 5-HT3A receptor (Stevens et al., 2005a). If these results are considered within the context of the classic Monod-Wyman-Changeux model for allosteric proteins (Monod et al., 1965), then our results imply that chloroform and halothane bind with higher affinity to 5-HT3A receptors in the open state versus the closed state, thus preferentially stabilizing the open state relative to the closed state. Incorporation of 5-HT3B subunits reduces anesthetic-induced gating enhancement because it reduces anesthetic binding affinity and/or conformational state selectivity. Similarly isoflurane produces little or no gating enhancement in either receptor subtype at clinically relevant concentrations because it possesses lower binding affinity and/or state selectivity than either chloroform or halothane.
Why do some anesthetics stabilize the open state whereas others do not? Our group's previous studies with both 5-HT3A (Stevens et al., 2005b) and 5-HT3AB receptors (Stevens et al., 2005a) using an EC10 concentration of 5-HT as agonist showed that there is a strong correlation between an anesthetic's ability to potentiate currents and its molecular volume. Specifically, only physically small volatile anesthetics (molecular volumes <120 Å3) potentiate 5-HT-evoked currents, whereas larger ones either had no effect or actually inhibited currents. This suggests that anesthetic binding to (and stabilizing of) the open state is sterically limited such that only inhaled anesthetics smaller than isoflurane (i.e., chloroform and halothane) significantly enhance channel gating efficacy.
The technique of using partial (i.e., inefficacious) agonists to distinguish between anesthetic affects on agonist binding versus channel gating is well established. Wu et al. (1994) used suberyldicholine, a partial agonist of the nAch receptor, to show that ethanol enhances channel gating (i.e., stabilizes the open state) of the nAch receptor, although a small increase in agonist affinity was also observed in that study. Suberyldicholine has also been used to show that isoflurane increases the apparent agonist affinity of the nAch receptor, by slowing the dissociation of agonist from its binding site (Raines and Zachariah, 2000).
Similarly, there is evidence that halothane slows agonist unbinding from the GABAA receptor, prolonging receptor activation (Li and Pearce, 2000). On the other hand, Harrison and colleagues used the combination of a partial agonist for the GABAA receptor, piperidine-4-sulfonic acid (P4S), and a mutant GABAA receptor with a gating defect, to demonstrate that isoflurane potentiates maximal P4S-evoked currents and thus acts, at least in part, by enhancing channel gating (Topf et al., 2003). In a separate report, the same research group also used a similar approach with wild-type GABAA receptors and P4S to show that propofol enhances channel gating of the GABAA receptor (O'Shea et al., 2000).
Lovinger and colleagues used DA to show that ethanol and trichloroethanol enhance channel gating in 5-HT3 receptors expressed in NCB-20 neuroblastoma cells (Lovinger et al., 2000). However, because NCB-20 cells express mRNA for both 5-HT3A and 5-HT3B subunits (Hanna et al., 2000), it is difficult to ascertain whether the agonist-evoked currents observed in that study were mediated by 5-HT3A receptors, 5-HT3AB receptors, or a combination of both. Our study using a heterologous expression system allowed us to define anesthetic actions on each receptor subtype separately, and our results demonstrate that the effects are clearly distinct.
In conclusion, the physically small, halogenated anesthetics chloroform and halothane decrease the agonist EC50 for 5-HT of homomeric 5-HT3A receptors by enhancing channel gating (i.e., stabilizing the open state relative to the closed state of the receptor) and without increasing agonist affinity. The incorporation of 5-HT3B subunits to produce heteromeric 5-HT3AB receptors markedly attenuates the ability of these anesthetics to enhance channel gating, illustrating the subunit dependence of these anesthetic effects. Isoflurane elicits only a minor gating enhancement effect for 5-HT3A receptors, which is abolished upon incorporation of 5-HT3B subunits to form 5-HT3AB receptors.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); nAch, nicotinic acetylcholine; DA, dopamine; MAC, minimum alveolar concentration; P4S, piperidine-4-sulfonic acid.
Address correspondence to: Dr. Ken Solt, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Edwards 505, Boston, MA 02114. E-mail: ksolt{at}partners.org
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