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Anesth Analg 2003;97:417-423
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Neither Spinal {gamma}-Aminobutyric Acid-A nor Strychnine-Sensitive Glycine Receptor Systems Are the Sole Mediators of Halothane Depression of Spinal Dorsal Horn Sensory Neurons

Masanori Yamauchi, MD, Steven G. Shimada, PhD, Hiroshi Sekiyama, MD, and J. G. Collins, PhD

Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut

Address correspondence and reprint requests to J. G. Collins, PhD, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St., PO Box 208051, New Haven, CT 06520-8051. Address e-mail to j.collins{at}yale.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Inhaled anesthetics depress the response of spinal dorsal horn low-threshold (LT) neurons to peripheral receptive field stimulation. Part of that depression may be mediated by anesthetic interactions with {gamma}-aminobutyric acid type A (GABAA) and strychnine-sensitive glycine inhibitory neurotransmitter systems. In this electrophysiological study, we attempted to antagonize halothane depression of LT neurons by administering bicuculline (a competitive GABAA antagonist) and/or strychnine (a competitive glycine antagonist) systemically, alone or in combination, to decerebrate, spinal cord-transected rats. We observed that both bicuculline and strychnine, alone or in combination, significantly but only partially reversed halothane depression of LT neuronal responses to receptive field stimulation. The inability of bicuculline and strychnine, alone or in combination, to completely reverse halothane depression suggests that although GABAA and glycine systems are involved in the observed halothane depression, additional mechanisms of action are also required for halothane depression of LT spinal sensory neurons.

IMPLICATIONS: The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, but not completely, by the anesthetic effects on {gamma}-aminobutyric acid type A and strychnine-sensitive glycine neurotransmitter systems.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In early studies of anesthetic effects on spinal sensory neurons, it was proposed that general anesthetic actions within the spinal cord may contribute to the production of anesthesia (1,2). In the 1990s, focus was again placed on the importance of anesthetic actions within the spinal cord (3–7). Spinal dorsal horn sensory neurons receive input from primary afferents and serve as the cells of origin for important ascending fiber tracts within the spinal cord (8–10). Perhaps anesthetic depression of those neurons may, by reducing the level of afferent input that reaches supraspinal regions of the central nervous system, contribute to the complex of behavioral changes associated with the state of general anesthesia.

Possible mechanisms of anesthetic action include anesthetic interactions with inhibitory neurotransmitter systems. Volatile anesthetics enhance currents at both {gamma}-aminobutyric acid type A (GABAA ) and glycine receptors (11–15) in a way that may be important to the production of general anesthesia (16,17). Activation of GABAA and strychnine-sensitive glycine receptors causes an influx of chloride ions, resulting in cell hyperpolarization and decreased excitability. Mason et al. (18) reported that spinal intrathecal administration of antagonists for GABAA receptors antagonized the immobilizing effects of halothane. Other investigators reported that the inhibition of glycine receptors antagonized the effects of halothane (19,20). Zhang et al. (21) have reported that the spinal intrathecal administration of antagonists for GABAA or glycine receptors increased the minimum alveolar anesthetic concentration (MAC) value of halothane by approximately 50%. In agreement with Zhang et al. (21), we found that both GABAA and strychnine-sensitive glycine receptors in the spinal cord mediate halothane depression of the response of spinal dorsal horn wide dynamic range (WDR) neurons to noxious peripheral receptive field (RF) stimulation (22).

Our laboratory has also been examining the possible involvement of inhibitory neurotransmitter systems on anesthetic depression of spinal sensory neurons that respond to nonnoxious peripheral stimuli. We have observed that the depression of low-threshold (LT) spinal dorsal horn neurons by halothane is due to spinal sites of drug action (23) and that GABAA and strychnine-sensitive glycine systems appear to mediate a significant portion of that depression (24,25). The primary purpose of this study was to examine the interaction between GABAA and strychnine-sensitive glycine receptor systems in their ability to mediate halothane depression of spinal LT neuronal responses to low-intensity peripheral RF stimulation. This work has been reported in abstract form (26).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With approval of our Institutional Animal Care and Use Committee, the extracellular activity of single spinal dorsal horn LT neurons was recorded in decerebrate, spinal cord-transected, male Sprague-Dawley rats (350–450 g; Harlan Sprague-Dawley, Inc., Indianapolis, IN). Anesthesia for surgical preparation of the animals was provided by 2%–3% halothane in 100% oxygen through a tightly fitting mask. The left external jugular vein was cannulated to allow for drug and fluid administration (lactated Ringer’s solution; 1 mL · kg-1 · h-1). The left carotid artery was cannulated for blood pressure monitoring. After tracheotomy, the trachea was intubated, and animals were mechanically ventilated. Animals were paralyzed with IV doses of pancuronium (0.2 mg). The end-tidal halothane concentration was monitored by a capnometer (Multinex; Datascope Co., Mahwah, NJ). End-tidal PCO2 and rectal temperature were monitored and maintained within physiological ranges. If mean arterial blood pressure decreased to <50 mm Hg, the experiment was discontinued, because in a previous study we observed that neuronal responses become smaller during severe hypotension (23). Decerebration by aspiration of cranial contents rostral to the mesencephalon made the animals permanently unconscious (verified by lack of response to noxious stimulus) and allowed us to obtain baseline data in the absence of an anesthetic drug. The spinal cord was transected at T2-3 via a small laminectomy, and the lumbar spinal cord (L2-5) was exposed by a separate laminectomy. Spinal cord transection allowed us to study drug effects at the level of the spinal cord without influences from supraspinal drug actions. After discontinuation of halothane administration, the dura of the lumbar spinal cord was opened and retracted to form a well, which was filled with mineral oil.

For the recording of single unit activity, a tungsten microelectrode (impedance, 10 M{Omega}; FHC Inc., Brunswick, ME) was inserted, by using a hydraulic micromanipulator, into the dorsal horn of the lumbar enlargement of the spinal cord and advanced until the activity of a single neuron could be isolated from other cells and distinguished from background activity. Neuronal testing did not begin until 30 min after the end of halothane administration for the surgical preparation of the animal. A single LT neuron was identified by the depth of the microelectrode (approximately 200–600 µm from the surface of the dorsal site of the spinal cord) and a characteristic response profile. LT neurons were identified as those neurons that were excited maximally by nonnoxious tactile stimulation. High-intensity mechanical stimuli can also activate these neurons, but the firing frequency was not greater than that seen with low-intensity stimuli.

After isolation and characterization of a single LT neuron, the baseline LT RF was mapped, and the neuron’s response to RF brushing was recorded. The edge of the RF area was determined as those points where light touch with a von Frey hair (5.15 g) elicited a response 50% of the time. The response to brushing was determined by measuring the number of action potentials evoked by light brush stimulation (1 s x 10 times) on the central area of the RF. Only one LT neuron was examined in each animal, to eliminate the cumulative effects of repeated drug administration and to maintain statistical independence among the neurons tested.

The GABAA receptor antagonist bicuculline and the glycine receptor antagonist strychnine (Research Biochemicals, Inc., Natick, MA) were dissolved in 0.01 M citric acid or water, respectively, and freshly prepared for each experiment. The first series of experiments involved control studies to examine the effects of each antagonist in the absence of halothane anesthesia. The effects of cumulative doses (0.3, 0.6, 1.0, and 2.0 mg/kg) of bicuculline or strychnine were initially tested, and subsequently, cumulative combined doses of the two drugs (0.3, 0.6, and 1.0 mg/kg of each) were tested to determine whether either the drugs by themselves, or in combination, caused changes in LT neuronal activity in the absence of halothane. The maximum combined dose of 1 mg/kg of each was chosen because we observed in pilot studies that maximum reversal of halothane depression was seen at that dose with no further increased reversal at larger combined doses.

The second series of studies involved an examination of the effects of each antagonist by itself on halothane-induced reduction of LT neuronal responses. After baseline values without halothane were determined, 1.1% halothane (1 MAC for rats) was administered for 30 min, and the neuronal activity was reevaluated. Next, cumulative doses (0.3, 0.6, 1.0, and 2.0 mg/kg) of bicuculline or strychnine were administered IV. Five minutes after each drug administration, neuronal activity was reevaluated. At the end of each experiment, halothane was discontinued, and at least 30 min later, when the end-tidal halothane concentration had been reduced to 0%, the RF size and neuronal activity were determined as a recovery value.

The third set of experiments involved an examination of the effects of administering both antagonists at the same time. Cumulative doses (0.3, 0.6, and 1.0 mg/kg) of an antagonist (bicuculline or strychnine) were administered in the presence of 1.1% halothane and the same dose of the other antagonist. Neuronal activity was observed in the absence of halothane, 30 min after the start of halothane administration, and at 5-min intervals after each combined cumulative dose of the antagonists in the presence of halothane.

LT neuronal recordings were converted to digital signals (CED 1401 Plus; Cambridge Electronic Design Ltd., Cambridge, UK) and stored in a computer. All data were subsequently analyzed with the Spike 2 software program (Cambridge Electronic Design Ltd.). For initial analysis, raw data were converted to percent of control. Evaluation of the effects of drugs, dose dependence, and time course were analyzed by analysis of variance for repeated measures followed by Scheffé tests or paired Student’s t-tests. Differences were considered to be significant when P < 0.05. All data are shown as mean ± SD.

For isobolographic analysis, raw data were converted to percent of maximum possible effect (%MPE) by using the following formula:


where control value was the initial drug-free response obtained before halothane, bicuculline, or strychnine. We assumed that the control value was the 100% MPE; if an antagonist achieved 100% MPE, then it would completely reverse the halothane-induced depression. The value after experimental exposure to halothane, "halothane value," was considered to be the smallest possible effect, or 0% MPE; neither antagonist would have caused any reversal of halothane-induced depression. Thus, the denominator "control value - halothane value" is the full range of possible values for the antagonism of the halothane-induced depression. "Antagonist value" is the value after any given antagonist is administered, and "antagonist value - halothane value" is the amount of reversal of halothane depression by the antagonist.

The %MPE normalizes the data and negates problems associated with variations in initial RF size and brush responses across different animals. The %MPE is the amount of reversal produced by bicuculline or strychnine of halothane depression of RF size or response to RF brushing.

We used fixed-ratio design isobolographic analysis (27) to determine the nature of the interaction between bicuculline and strychnine when both were administered simultaneously to antagonize the inhibitory effects of halothane on RF size and response to RF brushing. Briefly, the %MPE values were calculated for each dose of bicuculline and strychnine, and a least-squares linear regression line was calculated to define the dose-response relationship for each drug. That information was then used to construct the x and y axes for an isobologram. Because the maximum reversal by either antagonist in this study was approximately 60% MPE, we chose to conduct our isobolographic analysis in the linear range of the dose-response curve and selected 40% MPE as our point for isobolographic analysis. Using the linear regression data, we plotted an isobologram with doses of strychnine on the y axis and bicuculline on the x axis. We then plotted the 40% MPE dose for each drug on its respective axis. A line connecting those two points is, by definition, the line on which all theoretical combinations of bicuculline and strychnine that produce a 40% MPE lie.

The %MPE values were calculated for the combination experiments at doses of 0.3, 0.6, and 1.0 mg of each drug, and a least-squares linear regression was calculated for the data. With this regression, the experimental dose required for a 40% MPE was determined. A comparison of that experimental point with the theoretical 40% MPE value was used to indicate the nature of the interaction. We used methods described by Tallarida (27) to determine the statistical significance of the difference at the 95% level between the experimental and theoretical 40% MPE points.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In the absence of halothane, cumulative doses of bicuculline or strychnine did not alter the RF size determined by nonnoxious von-Frey filament stimulation (Fig. 1A) or the number of action potentials evoked by nonnoxious brush stimulation (Fig. 1B). The coadministration of bicuculline and strychnine also produced no significant effects on the RF size (Fig. 1A) or on the number of action potentials evoked by nonnoxious brush stimulation (Fig. 1B). We interpret these results to indicate that any effect of bicuculline or strychnine in the presence of halothane is a specific reversal of halothane-induced depression.



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  		Figure 1. Lack of effects of cumulative doses of bicuculline and strychnine, alone or in combination, on receptive field size (A) or brush-evoked neuronal activity (B). There were no significant differences in the neuronal activity observed in the presence or absence of the antagonists; n = 8–12. Data are presented as mean ± SD.

 
Halothane 1 MAC reduced the RF size from 13.3 to 3.2 cm2 (a reduction to 24% of the control value) (Fig. 2). Subsequent combined doses of bicuculline and strychnine significantly, but not completely, reversed that halothane effect. The combination of 1 mg of bicuculline and 1 mg of strychnine returned the RF size to 10.3 cm2 (77.4% of control). When halothane was discontinued, the RF recovered to 13.5 cm2 (101% of control).



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  		Figure 2. Example of drug effects on the receptive field (RF) area of a single low-threshold neuron. RFs were mapped on the skin of the hindquarter. The RF size was significantly decreased from the control value (100%) by 1 minimum alveolar anesthetic concentration (1.1%) of halothane (to 28% of control). The coadministration of bicuculline (bi; mg/kg) and strychnine (st; mg/kg) partially but significantly reversed the reduction of RF size (maximum, 77.4% of control at 1.0 mg/kg of each). With discontinuation of halothane, the RF recovered to the control value (recovery; 101%). Numbers in parentheses indicate the receptive field size (cm2).

 
As shown in Figure 3A, the response to brushing (B) in the absence of halothane elicited an average of 27 impulses per brush stroke. As shown in Fig. 3B, halothane reduced that response to nine impulses per brush stroke (33% of control). The coadministration of 1 mg/kg of bicuculline and strychnine reversed halothane depression of the brush-induced response to 22 impulses per brush stroke (81% of control) (Fig. 3C). With the discontinuation of halothane administration, the response per brush stroke returned to a value of 29 (Fig. 3D).



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  		Figure 3. Typical responses of brush-evoked neuronal activity of a low-threshold neuron. Each vertical stroke represents the occurrence of an action potential. A, Activity was evoked by brush stimulation (B), but not by noxious radiant heat stimulation (50 indicates 50°C for 8 s). Although activity was elicited by pinch (P), the response was no greater than that elicited by brush and occurred only at the beginning and end of the stimulus. B–D, As was seen with a change of receptive field size, the number of action potentials was markedly decreased (mean of 9 impulses per brush) from the control value (27 impulses per brush) by 1 minimum alveolar anesthetic concentration of halothane (B). C, The coadministration of 1 mg/kg of bicuculline and strychnine partially reversed (22 impulses per brush) the reduction of the neuronal activity. D, The neuronal activity recovered to the control value after discontinuation of halothane inhalation (29 impulses per brush).

 
Control responses were similar for cells in which bicuculline, strychnine, or their combination was studied (Table 1).


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  		Table 1. Mean Raw Control Data
 
A summary of depression by halothane and the antagonizing effects of bicuculline, strychnine, and their coadministration on RF size and brush-evoked neuronal activity is presented in Figure 4. Halothane significantly decreased RF size (Fig. 4A) and brush-evoked neuronal activity (Fig. 4B) to approximately 25% and 30% of control values, respectively (P < 0.01). In a dose-dependent fashion, bicuculline and strychnine partially antagonized the depressive effects of halothane. The maximum effects of bicuculline and strychnine were seen at 1 mg/kg. Those doses reversed halothane depression back to 57% ± 8% and 79% ± 6% of the control value for RF size and 65% ± 7% and 82% ± 7% of the control value for brush-evoked neuronal activity, respectively (P < 0.05 versus halothane alone or control value). There were no significant differences between the effects of 1 and 2 mg/kg of bicuculline or strychnine; this supports our previous observation that a maximum effect was seen at a dosage of 1 mg/kg.



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  		Figure 4. Effects of bicuculline, strychnine, and their coadministration in the presence of 1 minimum alveolar anesthetic concentration of halothane on the changes of receptive field size (A) and brush-evoked neuronal activity (B); n = 8–12; r = recovery from halothane anesthesia. Data are presented as mean ± SD. **P < 0.01 versus control (c); {dagger}P < 0.05 versus 0 mg/kg in each antagonist; ¶P < 0.05 versus the other groups at that dose.

 
The effects of combined doses of the two antagonists are also depicted in Figure 4. Of particular importance is the fact that even at the largest combined dosage (1 mg/kg of each antagonist), there was still a significant difference between the RF size (Fig. 4A) or the brush-evoked activity (Fig. 4B) at that point and the value at recovery after the termination of halothane. The combination of maximum doses of bicuculline and strychnine did not completely reverse the halothane-induced depression.

Isobolographic analysis confirmed the lack of additivity when bicuculline and strychnine were administered together. The results from the bicuculline/strychnine combination experiments were the same for both RF size and response to brush stimulation. In both cases, the experimentally derived dose for a 40% MPE (i.e., 40% reversal of halothane depression) was significantly larger, according to the modified Student’s t-test as described by Tallarida (27), than the theoretical dose derived from the log dose-response curves for the individual drug. This difference is shown graphically in the isobolograms for RF size (Fig. 5A) and brush response (Fig. 5B). Shown in each isobologram is the experimentally determined dose of a 50%:50% wt/wt combination for a 40% MPE response located above the theoretical 40% MPE line determined from the log dose-response curves for each individual drug. That point is the open diamond with horizontal and vertical error bars above the solid diagonal line in both (A) and (B). The fact that the experimental point is above the theoretical additive line (solid diagonal line connecting the calculated 40% MPE dose for strychnine [open square with vertical error bars next to the y axis] and the calculated 40% MPE dose for bicuculline [open square with horizontal error bars next to the x axis]) indicates that the interaction between bicuculline and strychnine in opposing the inhibitory effects of halothane was less than additive for both reduction of RF size and inhibition of the brush response.



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  		Figure 5. Isobolograms for the receptive field size (A) and brush response (B). In each graph, the 40% maximum possible effect (MPE) dose for each individual drug is shown ({square}) along with the theoretical 40% MPE line connecting these two points for the drug combination. • shows the theoretical additive point for the combination used in our study. {diamond} shows the experimentally determined value for that combination. Error bars represent SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
It is becoming apparent that general anesthetic actions on spinal sensory neurons are likely to contribute to anesthetic effects beyond the level of the spinal cord. There is value, therefore, in defining mechanisms by which anesthetics may alter spinal sensory processing. The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, in part, by drug interactions with GABAA and strychnine-sensitive glycine receptor systems but that other, yet to be identified, mechanisms of action are also involved.

Both GABAA and strychnine-sensitive glycine receptors are present in the spinal cord and modulate spinal sensory neurons (28,29). Activation of GABAA and strychnine-sensitive glycine receptors elicits an influx of chloride ions that produce hyperpolarization and decrease neuronal excitability, and volatile anesthetics enhance currents at both GABAA and glycine receptors (11–15). Of particular relevance to this study, Zhang et al. (21) have reported that the spinal intrathecal administration of antagonists for GABAA and strychnine-sensitive glycine receptors increased the MAC value of halothane by 50%. In agreement with the Zhang et al. study, we (22) have reported that both GABAA and strychnine-sensitive glycine receptors in the spinal cord partially mediate the halothane inhibition of the response of spinal dorsal horn WDR neurons to noxious peripheral RF stimulation.

An interesting result reported by Zhang et al. (21) was a plateau even when bicuculline and strychnine were combined. We have previously observed a plateau effect of both bicuculline and strychnine used alone when halothane depression of LT neurons is reversed (24,25) and therefore conducted these studies to determine the effects of combining the two antagonists.

The initial series of experiments in this study confirmed that bicuculline and strychnine, either alone or in combination, caused no change in the evoked activity of LT neurons at the doses studied. This is in keeping with our previous reports (24,25) and suggests that in the decerebrate, spinal cord-transected rat there is no tonic inhibitory modulation of lumbar spinal dorsal horn LT neurons by either GABAA or strychnine-sensitive receptor systems. In contrast, as we have recently reported, there appears to be tonic glycine modulation of lumbar spinal dorsal horn WDR neurons (22). The second series of experiments confirmed our previous observations that halothane depressed evoked activity of spinal dorsal horn LT neurons (23) and that the depression is partially mediated by GABAA and strychnine-sensitive glycine systems.

Results of the final set of experiments, in which cumulative doses of each antagonist were combined, provided results similar to those reported by Zhang et al. At the maximum combined dose of bicuculline and strychnine, the expected additivity was not apparent (Fig. 4). This lack of a complete reversal was not due to changes in the ability of the neurons to respond to the stimuli. This is evident from the complete recovery of response on termination of halothane.

The nature of the interaction between bicuculline and strychnine was further examined with isobolographic analysis. The lack of complete reversal by either drug alone limited our ability to perform an isobolographic analysis at the 100% MPE point. However, as demonstrated in Figure 5, at the 40% MPE, i.e., the point of 40% reversal of halothane depression, the interaction was subadditive, a trend that was apparent at the maximum dose of the two antagonists, where complete reversal was not observed.

The most likely explanation for the failure of the combination to completely reverse the halothane effect is that the depression of LT neuronal activity by halothane is only partially mediated by GABAA and strychnine-sensitive glycine systems. Modulation of afferent input to second-order neurons in the spinal cord is complex and not well understood. A possible reason for the failure of bicuculline and strychnine, when combined, to totally reverse the halothane-induced depression is differences in mechanisms by which primary afferent input is inhibited. Todd et al. (30) reported that GABAA and glycine receptors coexist at synapses in the rat spinal cord, after previous reports that many bouton in the spinal cord contain both GABA and glycine (31,32). It has also been demonstrated that both GABA and glycine can be co-released from interneurons in the spinal cord to activate both postsynaptic GABA and glycine receptors simultaneously (33,34). It appears that the ability of GABA and glycine to inhibit the same postsynaptic neuron may be age and location specific (35). Two laboratories (36,37) have reported that a significant population of primary afferents, including larger-diameter primary afferents that are likely to be important to this study, receive presynaptic inhibitory input from both GABA and glycine. We hypothesize that most primary afferents supplying information about touch to the neurons in our study were inhibited by that dual system and that either could produce maximum inhibition. If that were the case, additional reversal would not be seen when a second antagonist was added if the maximum reversal of inhibition (bicuculline reversal of the halothane inhibition) had already been reached.

The inability of bicuculline and strychnine to completely reverse the halothane-induced inhibition suggests that GABA and glycine are not the only inhibitory systems involved. As we recently reported (38), serotonin type 3 (5-HT3) receptors also appear to mediate a small portion of halothane depression of spinal dorsal horn neurons. 5-HT3 receptors have been reported to be expressed on primary afferents, including larger-diameter primary afferents that are likely to provide input to spinal dorsal horn neurons in this study. We hypothesize that at least a portion of the halothane depression that was not mediated by GABA and glycine was mediated by primary afferents under inhibitory control by 5-HT3 receptor systems. Although a direct comparison of the percentage of each involvement is not possible, the amount of halothane depression remaining to be reversed in this study (approximately 20%) is comparable to the 10%–15% reversal of halothane effects seen when a 5-HT3 antagonist was administered (39). Of note, the 5-HT3 receptor is in the same ligand-gated ion channel family as GABAA and glycine.


   Acknowledgments
 
This study was supported in part by National Institutes of Health Grants GM 44954 and NS 07136.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 3, 2003.





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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 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press