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Anesth Analg 2008; 107:885-889
© 2008 International Anesthesia Research Society
doi: 10.1213/01.ane.0000287646.85834.1a
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ANESTHETIC PHARMACOLOGY

Isoflurane Prevents Nicotine-Evoked Norepinephrine Release from the Mouse Spinal Cord at Low Clinical Concentrations

Thomas J. Rowley, BS, and Pamela Flood, MD

From the Department of Anesthesiology, Columbia University, New York City, New York.

Address correspondence to Pamela Flood, 630 West 168th St., New York City, NY 10032. Address e-mail to Pdf3{at}columbia.edu.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Volatile anesthetics inhibit nicotinic acetylcholine receptors at subanesthetic concentrations. In both animal and human studies, similar concentrations of volatile anesthetics have been associated with increased sensitivity to pain. Nicotinic analgesia is thought to involve the enhanced release of norepinephrine. These studies are intended as a "proof of concept" that alteration of the nicotinic facilitation of norepinephrine release is a potential mechanism for isoflurane-induced pronociception.

METHODS: We conducted our study using a murine lumbar spinal cord slice model. We evoked norepinephrine release with nicotine in the presence and absence of isoflurane. To identify the type of nicotinic receptor involved, we studied the effect of receptor and subtype-specific ligands and genetically engineered mice, which lacked the gene expression for the nicotinic β2 subunit. The amount of [3H]-norepinephrine released was measured under the different conditions.

RESULTS: Nicotine-facilitated norepinephrine release was significantly and maximally inhibited by isoflurane at concentrations that enhance pain sensitivity in vivo (0.38%). Facilitation of norepinephrine release was mimicked by the {alpha}7 selective agonist choline and inhibited in the presence of {alpha}-bungarotoxin, an {alpha}7-nicotinic selective antagonist. Facilitation of norepinephrine release was not different in animals lacking β2 subunits compared with matched controls.

CONCLUSIONS: Nicotinic facilitation of norepinephrine release in the spinal cord is inhibited by isoflurane at low clinically relevant concentrations. Because the net effect of noradrenergic tone in the spinal cord is inhibitory, the removal of this mechanism might be responsible for the enhanced pain sensitivity seen at these concentrations of isoflurane.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Volatile anesthetics inhibit nicotinic acetylcholine receptors in the central nervous system at low micromolar concentrations that persist after emergence from general anesthesia (1,2). These same minute concentrations of volatile anesthetic have been associated with increased sensitivity to pain in animal models (3,4) and human studies (5). The mechanism of volatile anesthetic enhancement of pain sensitivity is not known. According to one hypothesis, isoflurane inhibits nicotinic receptors that are a presynaptic "gain control" mechanism tonically regulating norepinephrine release in the spinal cord. There is extensive evidence for nicotinic facilitation of norepinephrine release in the spinal cord (6–10). It is further thought that the norepinephrine released has analgesic action through activation of {alpha}2-adrenergic receptors (9,11,12). In support of this hypothesis, both depletion of norepinephrine with neurotoxin and intrathecal injection of the {alpha}2-adrenergic antagonist, yohimbine, prevent nicotinic antinociception (13). These findings taken together raise the possibility that isoflurane enhances pain sensitivity by inhibiting nicotinic acetylcholine receptors in the spinal cord, with the net effect of reducing norepinephrine release. To determine whether this phenomenon occurs, we studied nicotine-evoked [3H]-norepinephrine release in a mouse spinal cord slice model.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
With the approval of the Columbia University Institutional Animal Care Committee (New York, NY), we studied female 129J mice aged 6-10 wk (Jackson Laboratories, Bar Harbor, ME). Additional studies were performed on genetically engineered C57B6 mice that lacked gene expression for the nicotinic β2 subunit and wild-type generation matched controls. These animals were developed by, and a gift from, Dr. J.P. Changeux, Institut Pasteur, Paris, France (14). The animals were group-housed, maintained in a temperature regulated environment, and had access to food and water ad libitum. The mice had intact ovaries, and the estrus stage was not tested, as preliminary experiments did not suggest that the estrus stage altered nicotine-induced release of [3H]-norepinephrine.

Preparation of Spinal Cord Slice
The mice were killed with CO2 and immediately decapitated. The lumbar region of the spinal cord was dissected together with surrounding tissue and transferred to ice cold dissecting buffer [25 mM glucose, 125 mM NaCl, 2.5 mM KCl, 26 mM NaHCO3, 12.5 mM NaH2PO4, 6 mM MgCl2, 1.5 mM CaCl2, 0.1 mM ascorbic acid, 0.1 mM pargyline, bubbled with 95% O2 to 5% CO2]. The spinal cord was removed en bloc from the L3-5 region of the spinal column. Immediately afterward, the spinal cord segment was placed in 2% low melting point agarose that was prepared in dissecting buffer (35°C) and the solution was chilled on ice. The agar-embedded spinal cord was prepared in a block and 300-µm-thick transverse slices were cut with a microtome (Leica Vt 1000 S, Leica Microsystems). The slices were transferred to 33°C buffer solution bubbled with 95% O2 to 5% CO2 for a 60-min recovery period.

After the recovery period, the slices were transferred to a cold perfusion buffer [25 mM glucose, 125 mM NaCl, 2.5 mM KCl, 26 mM NaHCO3, 12.5 mM NaH2PO4, 1 mM MgCl2, 2 mM CaCl2, 0.1 mM ascorbic acid, 0.1 mM pargyline, bubbled with 95% O2 to 5% CO2] (4°C) where the agar surrounding the slices was carefully removed manually. They were then incubated for 30 min in the perfusion buffer solution containing 10 µCi/mL [3H]-noradrenaline (28.0 Ci/mmol: Amersham), bubbled continuously with 95% O2 to 5% CO2, washed in buffer, and transferred to isolated perfusion chambers, which were warmed in a water bath at 37°C.

The spinal cord slice preparations were superfused with oxygenated perfusion buffer, maintained at 37°C for 30 min at 0.5 mL/min in a superfusion chamber (Harvard Apparatus, Holliston, MA). Samples were collected for 30 s every 2 min for 50 min. Baseline samples were collected for 14 min. During this period, norepinephrine release was stable. Identical buffer containing nicotine, with or without other drugs, was superfused during the following 16 min. During the onset of the nicotine application (t = 14-19), additional samples were collected every 30 s to ensure detection of a potentially short-lived effect. After this period (t = 30), the viability of the slice was tested by inducing norepinephrine release by depolarization with KCl (50 mM). Only slices that released norepinephrine in response to KCl were considered in our analysis.

Isoflurane was applied by running the 95% O2 to 5% CO2 gas line through a variable-bypass vaporizer (Isotec 4; Ohmeda, Madison WI). In control experiments, isoflurane concentrations were verified by gas chromatography (Gas Chromograph Series 580; Gow-Mac Instrument CO, Bethlehem, PA). Additional experiments were conducted in the presence of 50 µM CNQX (AMPA/Kainate antagonist), 50 µM APV (N-methyl-d-aspartate antagonist), 100 nM {alpha}-bungarotoxin ({alpha}7 selective nicotinic antagonist), 200 µM gabazine ({gamma}-aminobutyric acid (GABA)A antagonist), 40 nM CGP-55845 (GABAB antagonist), 1 µM strychnine (a glycine receptor antagonist), and 1 µM tetrodotoxin (sodium channel blocker). The CGP-55845 was purchased from Tocris Cookson, Ellisville, MO. All other drugs were obtained from Sigma-Aldrich, St. Louis, MO.

Samples were collected in 7-mL scintillation vials into which Ecolite (+) scintillation fluid (ICN; Cosa Mesa, CA) was added so not to exceed a load capacity of 30%. The radioactivity in each sample was measured in a liquid scintillation counter (Packard Tricarb, Packard Instruments; Meriden, CT).

Statistical Analysis
The release of norepinephrine was calculated by integrating the number of counts over time (i.e., the area under the curve, or AUC) using the trapezoidal method. The AUC is expressed as cpm/min tested. Agonist-evoked release of norepinephrine was calculated as the AUC after agonist administration—-AUC control (baseline response). Because the control data were not normally distributed, the amount of norepinephrine released under the different conditions were compared with the Mann-Whitney test. Concentration response data were tested with the Kruskal-Wallis test. P < 0.05 was considered significant.

Concentration response data were modeled using a standard Hill equation:



Formula 1

Max is the maximum response, nicotine is the administered nicotine concentration, nicotine50 is the nicotine concentration associated with half-maximal response, and the Hill coefficient defines the steepness of the concentration response relationship. Errors are expressed as standard error (sem). Data were modeled with Excel (Microsoft Corp., Redmond, WA). Graphics were made with Microcal Origin.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Nicotine-induced episodic, transient release of [3H]-norepinephrine from lumbar spinal cord slices (Fig. 1-inset). The half-maximal increase in [3H]-norepinephrine release occurred with 8.5 mM ± 5 mM nicotine and the Hill coefficient was 0.4 ± 0.1 (Fig. 1b). Based on these results, in the subsequent experiments, norepinephrine release was evoked with 1 mM nicotine. This dose was chosen because it was a midrange concentration causing [3H]-norpepinephrine release, and thus increases or decreases in release could be potentially identified.


Figure 129
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  		Figure 1. Concentration response for nicotinic facilitation of norepinephrine release in spinal cord slices. Nicotine facilitates the release of norepinephrine in spinal cord slices in a dose-dependent matter. The inset shows a typical response to nicotine and then KCl. Nicotine causes the initial release of norepinephrine that is self-limited. KCl-induced depolarization releases norepinephrine to confirm the viability of the slice. The amount of [3H]-norepinephrine released depends on nicotine concentration. When the data are fit to a standard Hill equation, the half-maximal increase in [3H]-norepinephrine release occurred with 8.5 mM ± 5 mM nicotine, and the Hill coefficient was 0.4 ± 0.1 (n = 82 slices from more than three animals per concentration).

 

Nicotinic facilitation of norepinephrine release was inhibited by isoflurane (Fig. 2), with maximum inhibition by 0.38% isoflurane. This inhibitory action of isoflurane is likely to be specific to nicotinic facilitation because isoflurane 0.38% did not affect global norepinephrine release induced by KCl (control 1340 ± 376 counts versus 1228 ± 364 counts with isoflurane 0.38%), and 0.75% isoflurane enhanced KCl induced norepinephrine release (control 1340 ± 376 counts versus. 5143 ± 520 counts with isoflurane 0.75%; P < 0.001, Mann-Whitney test).


Figure 229
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  		Figure 2. Isoflurane reduces nicotinic facilitation of norepinephrine release from the spinal cord. The presence of isoflurane reduces the amount of [3H]-norepinephrine released in response to 1 mM nicotine (P < 0.05, Kruskal-Wallis test, n = 59 slices from more than three animals per concentration. The reduction in [3H]-norepinephrine release was not greater in the presence of 0.75% than 0.38% isoflurane.

 

To identify the subtype of the neuronal nicotinic receptors responsible for facilitation of norepinephrine release, we studied nicotine-evoked release in the presence of an {alpha}7 selective nicotinic antagonist ({alpha}-bungarotoxin) (15) and determined whether choline, an {alpha}7 selective agonist (16), also evoked norepinephrine release. Choline (20 mM)-facilitated norepinephrine release and nicotine-facilitated norepinephrine release were significantly reduced in the presence of {alpha}-bungarotoxin, suggesting a role for the {alpha}7 nicotinic subunit in norepinephrine release (Fig. 3A, Mann-Whitney test, P < 0.001). In a separate study, nicotine-evoked release of [3H]-norpepinephrine was studied in nicotinic β2 knockout mice and their generation-matched wild-type controls. There was no difference in the amount of norepinephrine release between β2 knockout mice and their generation-matched wild-type controls (Fig. 3B).


Figure 329
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  		Figure 3. The nicotinic receptors that mediate norepinephrine release likely contain an {alpha}7 subunit and no β2 subunit. (A) The {alpha}7 selective nicotinic agonist choline (10 mM) facilitates release of [3H]-norepinephrine that is not different from the amount released in response to nicotine (1 mM, n = 10). The presence of the nicotinic receptor antagonist {alpha}-bungarotoxin (100 nM) reduced [3H]-norepinephrine in response to 1 mM nicotine (P < 0.001, Mann-Whitney U-test, n = 18). (B) The amount of [3H]-norepinephrine that is released in response to 1 mM nicotine is not different between mice that lack expression of β2 nicotinic subunits and their generation matched wild-type controls (n = 34).

 

We conducted a series of experiments designed to determine whether polysynaptic circuits, including excitatory or inhibitory interneurons, are important in nicotine-evoked norepinephrine release in the spinal cord. The presence of CNQX (50 µM), APV (50 µM), gabazine (200 µM), CGP (40 nM), strychnine (1 µM), or tetrodotoxin (1 µM) had no effect on the amount of nicotine-evoked norepinephrine release (Table 1).


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  		Table 1. Evidence for a Direct Effect of Nicotine on Noradrenergic Axon Terminals

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Enhanced release of norepinephrine in the spinal cord is thought to be one mechanism by which nicotine induces analgesia (9,11). We have demonstrated nicotinic facilitation of norepinephrine release in our model of mice lumbar spinal cord slices. Previous studies with this preparation have demonstrated that nicotine-induced norepinephrine release is by exocytosis, as it is calcium dependent (10). Furthermore, it is specifically due to activation of nicotinic receptors, as it is inhibited by the nicotinic antagonists dihydro-β-erythroidine (selective for heteromeric nicotinic receptors) and, less potently, methyllycaconitine (selective for {alpha}7 containing nicotinic receptors)(6).

Under the conditions used in this in vitro assay, the level of tonic norepinephrine release was very low, approximately 44 cpm. Of course, in spinal cord slices, both tonic excitatory and inhibitory activity that would be present in an intact animal are interrupted. However, evidence from our laboratory (13) and others’ (17) suggests that tonic norepinephrine release is significant and affects the pain-enhancing characteristics of isoflurane.

Enhanced pain sensitivity has been observed at low concentrations of isoflurane that would be present on emergence from general anesthesia (3,4). This effect is related to norepinephrine release because it does not occur after norepinephrine depletion with the neurotoxin DSP-4, or after blockade with the noradrenergic {alpha}2 receptor blocker, yohimbine (13). As a proof of principle, we measured the effect of isoflurane on nicotine-facilitated norepinephrine release in spinal cord slices. Isoflurane reduced nicotine-evoked norepinephrine release, and the effect was maximal at subanesthetic concentrations that cause hyperalgesia (Fig. 2). The action of isoflurane is specific for nicotinic facilitation because KCl-evoked release is not affected by isoflurane.

We found that facilitation of norepinephrine release was likely mediated by a nicotinic receptor that contains the {alpha}7 subunit. We were surprised by evidence for involvement of {alpha}7-type nicotinic receptors. In studies of intact animals, the {alpha}4β2 selective nicotinic agonist metanicotine evoked norepinephrine release similar to that observed in our experiments (6). Therefore, activation of {alpha}4β2 type nicotinic receptor can enhance norepinephrine release in the spinal cord. The nicotinic β2 knockout mice that we studied almost completely lack high affinity nicotine binding thought to be due to {alpha}4β2 nicotinic receptors (14). Thus, we expected the β2 knockout mice to have less nicotinic facilitation of [3H]-norepinephrine release than the wild-type controls. This was not the case (Fig. 3B). Perhaps the facilitation of norepinephrine release seen by Li et al. occurred because of activation of a descending circuit that had been interrupted in our spinal cord slice preparation, but that was present in the intact animal. Since the descending noradrenergic axons were necessarily cut in our model, it is possible that the receptors activated by metanicotine are more cephalad, explaining the absence of a β2 genotype effect in our model.

In contrast, we have demonstrated that choline, a breakdown product of acetylcholine that selectively activates {alpha}7 containing nicotinic receptors, can enhance norepinephrine release in spinal cord slices (Fig. 3A). There is evidence that activation of {alpha}7 subunit containing nicotinic receptors also induces monoaminergic facilitation in dorsal raphe neurons (7). Although the bulk of evidence points to {alpha}4β2 activation in nicotinic analgesia (18), nicotinic agonists selective for {alpha}7 containing nicotinic receptors can reduce pain sensitivity when injected intrathecally (19) and intracerebroventricularly (20). The sensitivity of nicotinic receptors containing an {alpha}7 subunit to inhibition by isoflurane is surprising, given the relative insensitivity of nicotinic receptors composed solely of {alpha}7 subunits studied in in vitro systems (1,21). This apparent paradox might be explained by the fact that only homomeric {alpha}7 nicotinic receptors have been studied and found to be relatively insensitive to isoflurane. The presence of heteromeric nicotinic receptors that contain {alpha}7 in vivo is not in doubt (22–25), but the sensitivity of such receptors to isoflurane has not been studied in vitro. Because we have not studied a full range of choline concentrations, we cannot determine whether the effect of nicotine can be fully recapitulated by choline. It is possible that another type of nicotinic receptor also contributes to nicotine-evoked norepinephrine released that does not contain a β2 or {alpha}7 subunit.

Our studies suggest that the facilitation of [3H]-norepinephrine release obtained through activation of {alpha}7 containing nicotinic receptors is likely to be due to direct inhibition of receptors on the noradrenergic axons. Neither inhibitors of excitatory transmission nor inhibitory transmission affected nicotinic facilitation of norepinephrine release.

In summary, we have demonstrated that nicotine facilitates the release of norepinephrine in slices of lumbar spinal cords. Isoflurane significantly reduces the facilitatory effect of nicotine through an {alpha}-bungarotoxin sensitive pathway. Nicotinic facilitation is significantly inhibited at concentrations of isoflurane that increase pain sensitivity. As such, the inhibition of nicotinic receptors in the lumbar spinal cord is a potential mechanism for the pain enhancement that occurs at low concentrations of isoflurane.


   Footnotes
 
Accepted for publication August 13, 2007.

Dr. Flood is the wife of Dr. Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James Bovill, former Section Editor of Anesthetic Pharmacology, and Dr. Shafer was not involved in any way with the editorial process or decision.

This work was presented, in part, at the meeting of the International Anesthesia Research Society in Tampa, Florida, March 15-16, 2004.

Reprints will not be available from the author.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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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 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press