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Anesth Analg 2002;94:1495-1499
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Acetylcholine Receptors Do Not Mediate Isoflurane’s Actions on Spinal Cord In Vitro

Shirley M. E. Wong, MS*, James M. Sonner, MD{dagger}, and Joan J. Kendig, PhD*

Departments of Anesthesia, *Stanford University School of Medicine, Stanford; and {dagger}University of California at San Francisco, San Francisco, California

Address correspondence to Dr. Joan J. Kendig, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305-5117. Address e-mail to kendig{at}stanford.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Extensive studies on anesthetic mechanisms have focused on the nicotinic acetylcholine receptor, and to a lesser extent on the muscarinic receptor. We designed the present study to test the hypothesis that cholinergic receptors mediate some of the depressant actions of a volatile anesthetic in rat spinal cord. The cord was removed from 2- to 7-day-old rats and superfused in vitro; ventral root potentials were evoked by stimulating a lumbar dorsal root and recording from the corresponding ipsilateral ventral root. Both nicotine and muscarine depressed the nociceptive-related slow ventral root potential (sVRP). The nicotinic antagonists mecamy-lamine, methyllycaconitine, dihydro-ß-erythroidine, and the muscarinic antagonist atropine blocked the depressant effects of the respective agonists. Isoflurane 0.3 mini- mum alveolar anesthetic concentration depressed the sVRP area to approximately 40% of control. None of the antagonists changed the extent of isoflurane depression of the sVRP. The depressant actions of cholinergic agonists suggest that cholinergic receptors are important in spinal neurotransmission, but the lack of interaction between antagonists and isoflurane suggests that cholinergic receptors have little part in mediating the actions of this anesthetic in spinal cord. Because minimum alveolar anesthetic concentration is determined primarily in spinal cord, cholinergic receptors may be eliminated as molecular targets for this anesthetic end-point.

IMPLICATIONS: Neither nicotinic nor muscarinic acetylcholine receptor antagonists altered spinal cord actions of isoflurane, suggesting that these receptors have little role in isoflurane actions in spinal cord. Cholinergic receptors thus may be eliminated as molecular targets in determining the anesthetic end-point of immobility in response to a noxious stimulus (minimum alveolar anesthetic concentration).


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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The nicotinic acetylcholine (ACh) receptor has been the focus of numerous studies on mechanisms of anesthesia at the molecular level (1–15). This receptor has served as a model for other ligand-gated receptors and, because of its sensitivity to anesthetics and its wide distribution in the nervous system, as a plausible mediator of anesthesia. To a lesser extent, muscarinic cholinergic receptors have also been subjects of study with respect to anesthesia (16).

The spinal cord has the predominant role in determining the ability of volatile anesthetics to suppress movement in response to a noxious stimulus (17,18). Thus, the spinal cord is the relevant part of the central nervous system to examine the mechanisms of anesthetic action that underlie this anesthetic end-point. Spinal cord nicotinic receptors mediate the excitatory input to inhibitory interneurons that provide inhibitory feedback to motor neurons, and thus might be implicated in the ability of inhaled anesthetics to suppress movement in response to noxious stimuli. Both nicotinic and muscarinic ACh receptors have been implicated in analgesia (19,20).

We previously documented the depressant effects of volatile anesthetics on evoked responses in intact spinal cords from neonatal rats and mice (21–23). Enflurane actions are mediated in part by the enhancement of {gamma}-aminobutyric acid type A receptor activity; the block of receptors by bicuculline attenuates the ability of enflurane to depress ventral root evoked responses (23). In the present study, a similar strategy, using nicotinic and muscarinic antagonists, was used to test whether ACh receptors have a role in mediating the actions of isoflurane on ventral root evoked responses in spinal cords from rats.

Because of the evidence for analgesic properties of ACh receptors in spinal cord, and a possible relationship between analgesia and minimum alveolar anesthetic concentration (MAC), the studies were done on the nociceptive-related slow ventral root potential (sVRP) (24–26). The studies were designed to parallel those performed on MAC in vivo (27). Because different subunit types might support functionally opposite actions, we also studied additional subunit-specific antagonists.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
Using a protocol approved by Stanford’s Animal Care and Use Committee, spinal cords were removed from newborn (2 to 7 days old) Sprague-Dawley rat pups. The experiments were performed using previously described methods (28). Including nonviable cords and incomplete experiments, approximately 100 animals were killed for the studies reported herein, and the like number of cords removed. Briefly, rats were anesthetized with halothane until loss of movement response to tail pinch, then decapitated under anesthesia. The spinal cord was dissected and placed in a recording chamber. Isolated spinal cords were superfused at a rate of 4 mL/min with artificial cerebrospinal fluid (ACSF) of the following composition in mM: NaCl 123, KCl 5, Na2PO4 1.2, MgSO4 1.3, NaHCO326, CaCl22, and dextrose 30. The ACSF was equilibrated with 95% O2-5% CO2 yielding a stable pH of 7.3–7.4 at a temperature between 27° and 28°C, the physiologic temperature of rat pups of this age when not in close contact with the mother. A stimulating electrode was placed on a lumbar dorsal root and a recording electrode on the corresponding ipsilateral ventral root to record the sVRP. Constant-current square-wave stimuli, 0.2 ms in duration, were administered every 50 s throughout the experiments. Responses were digitized, averaged as groups of five, and stored for later analysis. Area under the curve was measured, and the results were calculated as percentage change with each preparation normalized to its own control.

Cholinergic agents were diluted in the ACSF to the desired concentration. Isoflurane was made up as a saturated solution in ACSF and diluted to the desired concentration just before administration via a closed system to minimize evaporative loss. Isoflurane concentrations in the recording chamber were measured by using gas chromatography.

To test the involvement of ACh receptors, we administered isoflurane alone to one group of preparations, and antagonist followed by isoflurane in the continued presence of antagonist to a second group. Isoflurane effects were measured at 30 min of exposure in both groups. Statistical significance of differences between anesthetic actions alone and in the presence of an antagonist was determined by using t-test, with the level of significance set at P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Actions of Cholinergic Agonists and Antagonists in Spinal Cord
Nicotine (1 µM) exerted a pronounced depressant effect on spinal cord-evoked sVRP (Fig. 1, A and C) (P < 0.0001 compared with control). At this concentration, depression was monotonic and stable. Larger concentrations produced an initial profound depression that was quickly succeeded by partial recovery (data not shown), probably reflecting the rapid desensitization characteristic of nicotinic receptors. Muscarine (0.1 µM) also depressed the response (Fig. 1, B and D) (P < 0.0001 compared with control) At this concentration, muscarinic depression was monotonic. Depression by both agents was partially reversible on washing with a drug-free solution. At the concentrations used in the present study, the nicotinic antagonists mecamy-lamine, which blocks both {alpha}4ß2 (type II) and {alpha}3ß4 nicotinic receptors (type III), dihydro-ß-erythroidine (dHßE), specific to the {alpha}4ß2 subunit combination, and methyllycaconitine (MLA), specific to {alpha}7 receptors (29), had little effect by themselves, nor did the muscarinic antagonist atropine (P > 0.05). Examples for mecamylamine (80 µM) and atropine (0.1 µM) are shown in Figure 2, A and B. The concentrations of antagonists were selected from reports in the literature of 50% effective concentrations for in vitropreparations comparable to the isolated spinal cord (30,31). To assess the effectiveness of these antagonist concentrations in blocking spinal cholinergic receptors, we tested their ability to block the depressant actions of exogenously applied nicotine or muscarine. As shown in Figure 1, C and D, nicotine 1 µM and muscarine 0.1 µM each produced approximately a 50% depression of the sVRP. Mecamylamine (80 µM) and atropine (0.1 µM) effectively blocked the depressant effect of these agonist concentrations (Fig. 2,C and D).



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  		Figure 1. Effects of cholinergic agonists on slow ventral root potentials (sVRP). A and B, Raw data showing the effects of nicotine (1 µM) and muscarine (musc) on the sVRP. Data are averages of five traces. C, Nicotine (1 µM) depresses the sVRP area by approximately 50% (P < 0.0001 compared with control). The depression is monotonic and stable at this concentration, and is only slowly reversed on washing with artificial cerebrospinal fluid (ACSF). D, Muscarine (0.1 µM) also depresses the sVRP by approximately 50% (P < 0.0001 compared with control), and the depression is only partially reversed on washout. Data points are averages of three experiments, and error bars are SEM.

 


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  		Figure 2. Cholinergic antagonists have little effect by themselves on the slow ventral root potentials (sVRP) but completely antagonize the depressant effects of agonists. A, Mecamylamine (MCA) (80 µM) and B, atropine (atr) (0.1 µM) were applied at the points indicated by the arrows. There was no significant difference from control (P > 0.05). C, Mecamylamine (80 µM) was present throughout the experiments and nicotine (nic) (1 µM) was applied at the point indicated by the arrow. D, Atropine (0.1 µM) was present throughout the experiment and muscarine (musc) (0.1 µM) was applied for the period beginning at the arrow. A comparison of C and D with Figure 1, A and B shows that these antagonist concentrations effectively antagonized exogenous agonists. Data points are means of four experiments, and error bars are SEM.

 
Isoflurane
We previously reported that isoflurane depressed the sVRP (21). A concentration equivalent to 0.3 MAC was chosen for these studies to permit either a positive or a negative interaction with cholinergic antagonists to be detected; at 1 MAC, the sVRP is so deeply depressed that an attenuation might have been overwhelmed (21). There was no significant attenuation of isoflurane’s depressant effect by mecamylamine, dHßE, MLA, or dHßE and MLA combined (Fig. 3, A and B) (P > 0.05). Similarly, there was no interaction between atropine and isoflurane’s depressant effects (Fig. 3C) (P > 0.05).



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  		Figure 3. Cholinergic antagonists do not significantly alter the potency of isoflurane. Isoflurane at a concentration equivalent to 0.3 minimum alveolar anesthetic concentration was applied at the points indicated by the arrows. A, Isoflurane (iso) alone and in the presence of mecamylamine (MCA) (80 µM). B, Isoflurane alone and in the presence of a combination of methyllycaconitine (MLA) (0.2 µM) and dihydro-ß-erythroidine (dHßE) (20 µM). The slight attenuation of isoflurane’s depressant actions was not significant (P > 0.05). C, Isoflurane alone and in the presence of atropine (atr) (0.1 µM). Data points are means of four to six experiments, and error bars are SEM. SVRP = slow ventral root potential.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Circuits in the Spinal Cord
Stimulating a dorsal root at a strength sufficient to recruit small-diameter afferent fibers activates interneurons in the dorsal horn that make synaptic connections with motor neurons. The sVRP is generated in the motor neurons as a result of this polysynaptic input. The transmitters that mediate it include glutamate acting on N-methyl D-aspartate receptors and a variety of transmitters that act on second-messenger coupled receptors, including NK1, NK2, and metabotropic glutamate (22) (JJK, unpublished data). The sVRP is a very slow depolarizing potential that depends on activation of high-threshold slowly conducting afferents in a peripheral nerve or dorsal root (26,32). Other characteristics that relate this response to nociceptive neurotransmission are evocation by true noxious stimuli (24) and sensitivity to analgesics, including opioids and {alpha}2 adrenoceptor agonists (21,28).

Cholinergic Receptors in Spinal Cord and Effective Antagonist Concentrations
Although a previous study (33) had suggested that substance P-evoked ACh release facilitated the sVRP, the depressant actions of exogenously applied nicotinic and muscarinic agonists in the present study show that the overall functional role of cholinergic receptors in spinal cord is predominantly inhibitory. The lack of effect of the antagonists by themselves suggests that there is little tonic cholinergic inhibition of these responses in the cord. Antagonist concentrations that we used equaled the 50% effective concentrations reported for preparations similar to the isolated rat spinal cord (30,31). The appropriateness of these concentrations was shown by their ability to completely antagonize exogenous agonist concentrations that produced approximately 50% depression of the response area. Thus, any anesthetic responses mediated by these receptors should have been modified by the antagonists. The relationship of the concentrations used in the present study to the spinal cord concentrations achieved by administration in vivo are uncertain because of the different methods of administration. However, it is estimated that the intrathecal atropine concentrations were 0.4 to 12 µM (27), and perhaps somewhat smaller at the site of action in the cord.

The Role of Cholinergic Receptors in Anesthesia
The results are consistent with the hypothesis that, although cholinergic receptors have an important role in normal spinal cord physiology, they do not have a material role in mediating the depressant actions of isoflurane. Because cholinergic agonists predominantly act as depressants of the sVRP, an attenuation of anesthetic depressant actions by antagonists would be predicted only if the anesthetic enhanced currents through these receptors, as is the case for {gamma}-amino-butyric acid type A and glycine receptors, or if anesthetics reduced ACh release. Ethanol, in fact, enhances currents at some subtypes of nicotinic receptors, whereas volatile anesthetics either inhibit them or show no effect (14,15,34,35). Because there is little tonic cholinergic inhibition under the present experimental conditions, an action on ACh release would probably not be observed.

The results are also consistent with the finding that neither mecamylamine nor atropine alters isoflurane MAC in rats (27), nor does mecamylamine alter MAC in mice (36). The congruence between the results in vivo and in spinal cord in vitro supports the relevance of spinal cord-evoked responses to the spinal pathways that underlie the withdrawal reflexes abolished by inhaled anesthetics.

Negative findings seldom have the impact of positive results. However, in view of the universe of plausible targets that have been proposed in theories of anesthetic mechanisms, a winnowing out of some may allow a greater focus on relevant targets. Although they may have a role in other anesthetic end-points such as amnesia, it seems that cholinergic receptors do not mediate the anesthetic end-point of immobility in response to a noxious stimulus.


   Acknowledgments
 
Supported by National Institutes of Health Grants GM47818 and NS13108 to JJK.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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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