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ANESTHETIC PHARMACOLOGY

Acetylcholine Receptors Do Not Mediate the Immobilization Produced by Inhaled Anesthetics

Edmond I Eger, II, MD^*, Yi Zhang, MD^*, Michael Laster, DVM^*, Pamela Flood, MD, Joan J. Kendig, PhD, and James M. Sonner, MD^*

*Department of Anesthesia and Perioperative Care, University of California, San Francisco; Department of Anesthesiology, Columbia University, New York; and Department of Anesthesia, Stanford University, California

Address correspondence and reprint requests to Edmond I Eger II, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere@ anesthesia.ucsf.edu.

	Abstract

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Acetylcholine receptors transmit excitatory impulses, are broadly distributed throughout the central nervous system, and are particularly sensitive to the depressant effects of inhaled anesthetics. Thus these receptors are potential mediators of the immobility produced by inhaled anesthetics. We tested this potential in rats by giving intraperitoneal atropine, scopolamine, and mecamylamine to block muscarinic (atropine and scopolamine) and neuronal nicotinic (mecamylamine) acetylcholine receptors. Block with scopolamine (up to 100 mg/kg), atropine (10 mg/kg), mecamylamine (up to 4 mg/kg), or atropine (10 mg/kg) plus mecamylamine (up to 4 mg/kg) did not significantly decrease the isoflurane concentration required to suppress movement to noxious stimulation (minimum alveolar anesthetic concentration). We also gave atropine intrathecally, finding that the infusions that did not cause permanent paralysis produced slight or no decreases in the minimum alveolar anesthetic concentration. We conclude that acetylcholine receptors do not seem to play a role as mediators of immobilization by inhaled anesthetics.

IMPLICATIONS: Inhaled anesthetics produce two crucial effects: amnesia and immobility in the face of noxious stimulation. Block of muscarinic and neuronal nicotinic acetylcholine receptors in rats does not significantly decrease the isoflurane concentration required to suppress movement to stimulation. Thus, acetylcholine receptors do not seem to play a major role as mediators of the immobilization produced by inhaled anesthetics. Their capacity to mediate other effects of inhaled anesthetics (e.g., amnesia) remains to be tested.

	Introduction

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Several factors suggest that acetylcholine receptors may mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation. Such receptors provide excitatory neurotransmission throughout the central nervous system (1,2). In vitro, inhaled anesthetics depress the response of both muscarinic (3) and neuronal nicotinic (4,5) receptors to acetylcholine. The muscarinic blocking drugs atropine and scopolamine have central nervous system effects at larger doses (e.g., 1–10 mg/kg) that produce hallucinations and coma in humans (6). Atropine reverses the antinociception induced by intrathecal injection of neostigmine (7). Similarly, injection of scopolamine, but not mecamylamine, into the rostral ventromedial medulla decreases the analgesia produced by ß-endorphin or morphine (8). However, intrathecal injection of atropine, scopolamine, or mecamylamine does not alter the allodynia produced by ligation of spinal nerves (9). Activation of spinal nicotinic receptors by a drug such as epibatidine can produce an algogenic response that is blocked by mecamylamine but not by atropine (10).

Injection of carbachol into the pontine reticular nucleus decreases the minimum alveolar anesthetic concentration (MAC) of halothane (11). Finally, injection of nicotine into the interpeduncular nucleus in rats prolongs recovery from anesthesia with halothane, and pretreatment with 2 mg/kg of mecamylamine antagonizes this effect (12). These observations (and many more not cited) suggest that cholinergic receptors may mediate the capacity of inhaled anesthetics to produce immobility in response to noxious stimulation. The present study examined this possibility.

	Methods

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The Committee on Animal Research of the University of California, San Francisco, approved our study of male Sprague-Dawley rats weighing 275–325 g from Charles River Laboratories (Crl:CD^®(SD)BR, Hollister, CA). Rats were housed two per cage in our animal care facility under 12 h light:dark cycles and had continuous access to standard rat chow and tap water for 3–7 days before the study. Two sets of studies were performed. The first measured the MAC of isoflurane required to eliminate movement in response to a noxious stimulus (tail clamp) after intraperitoneal injection of drugs blocking muscarinic and nicotinic acetylcholine receptors. The second measured the effect of an intrathecal administration of atropine on isoflurane MAC.

MAC for isoflurane was measured concurrently in four to eight rats in each experiment. Each rat was placed in a clear plastic tube through which oxygen flowed at >0.5 L/min. The tube was capped at each end with rubber stoppers pierced with holes that allowed passage of the oxygen, the entry of a temperature probe, and the exit of the rat’s tail. Isoflurane was added to the stream of oxygen, and a rectal temperature probe was inserted. Temperature was maintained between 36°C and 38.5°C by external heating (infrared lamps) or cooling (application of ice). The isoflurane concentration in the cylinder, monitored with an infrared analyzer (Capnomac II; Datex, Helsinki, Finland), was decreased to a concentration (1.0%–1.2%) that permitted movement in response to a 1-min (less if the rat moved) application of a tail clamp, with continuous movement of the tail clamp. The concentration was sustained for 30 min before tail clamp application. After finding that movement occurred, a gas sample was obtained and analyzed using gas chromatography. The isoflurane concentration was increased by approximately 15%–20% of the preceding value, and the process was repeated until the rat did not respond to the tail clamp. MAC for the individual rat was estimated as the average of the largest concentration permitting movement and the next largest concentration. The mean and SD for the group of rats were calculated for each study with a particular drug.

Seven studies of the effect of intraperitoneal injection of antagonists on MAC were performed. The first was a determination of a control MAC. Approximately 0.3 mL of normal saline was injected intraperitoneally during the first period of equilibration. The rats were allowed to recover for at least 3 days between the determinations of MAC in each succeeding study. In the next study, we prepared the rats as above, but during the first period of equilibration we injected 10 mg/kg of atropine intraperitoneally. In succeeding studies, we injected 2 mg/kg of scopolamine, 4 mg/kg of mecamylamine, 2 mg/kg of mecamylamine plus 10 mg/kg of atropine, 4 mg/kg of mecamylamine plus 10 mg/kg of atropine, and saline (a repeat control measurement) intraperitoneally. The doses of atropine and scopolamine selected were arbitrary. Our intent was that they be excessive–that they block most, if not all, muscarinic and nicotinic receptors. The doses of atropine and mecamylamine far exceeded those required to block muscarinic effects of acetylcholine in humans (13). The doses of mecamylamine are similar to the dose that, in mice, prevents prostration in response to the injection of nicotine for at least 3 h (Flood, unpublished data).

Because these studies produced negative results (no change in MAC), we studied a second set of four rats given still larger doses of scopolamine. The pattern of study differed in that a control MAC was obtained, and then MAC was redetermined after intraperitoneal injection of scopolamine (10 mg/kg in one study and 100 mg/kg in a second study).

In a second series of experiments, we studied the effect of the intrathecal infusion of atropine on isoflurane MAC. Rats were anesthetized with isoflurane, and a 32-gauge polyurethane catheter (Micor Inc, Allison Park, PA) was placed through the atlantooccipital membrane after the method of Yaksh and Rudy (14). The catheter was threaded caudally 6–8 cm towards the lumbar sac (length depended on the size of the rat). The other end of the catheter was tunneled to and out the ear where it was sutured in place. Rats were allowed to recover from anesthesia and surgery for at least 1 day before the study.

On a succeeding day, the rats were placed in individual chambers, as described in the above studies, that used intraperitoneal injections. Isoflurane was administered to produce anesthesia, and MAC was determined while artificial cerebrospinal fluid (aCSF) was infused intrathecally at an inflow rate of 1 µL/min. Stock solutions (Stock) for aCSF were made daily. Stock 1 was a mono-valent solution made by adding NaCl 3.6963 g, NaHCO₃ 1.1551 g, KCl 0.0895 g, KH₂PO₄ 0.0340 g, and Na₂SO₄ 0.0355 g in deionized, distilled water to a volume of 500 mL. Stock 2 was a di-valent solution made from CaCl₂ · 2H₂O 0.8086 g and MgCl₂ · 6H₂O 0.8437 g in deionized, distilled water to a volume of 10 mL. To make aCSF, 25 mL of Stock 1 was added to 0.0266 g of glucose, adjusted to a pH value of 7.4 with bubbles of CO₂ for approximately 10 min, and added to 50 µL of di-valent Stock 2, giving a final composition of 154.7 mmol/L of Na⁺, 0.82 mmol/L of Mg²⁺, 2.9 mmol/L of K⁺, 132.49 mmol/L of Cl^-, 1.1 mmol/L of Ca₂⁺, and 5.9 mmol/L of glucose at a pH value of 7.4.

After determining MAC during infusion of aCSF, the concentration of isoflurane was held at the concentration that produced immobility in all rats. In sets of four rats, we then administered atropine in aCSF into the lumbar intrathecal space at an inflow rate of 1 µL/min at concentrations of 2.5 mg/mL, 10 mg/mL, 20 mg/mL, or 40 mg/mL for 50 min. The atropine concentration was then decreased to half the initial concentration, and this concentration was infused at an inflow rate of 1 µL/min for the remainder of the study. MAC was measured as described above both with decreasing and increasing concentrations of isoflurane.

All MAC determinations during intrathecal infusions evaluated movement of both the forelimbs and the hind limbs. That is, we obtained three estimates of MAC: one determined from hind limb movement, one from forelimb movement, and one from both. After completing the determinations of MAC, the isoflurane administration and the intrathecal infusion were discontinued. The rats were examined for the ensuing 2–5 h and the next day for their ability to move their lower extremities and to respond to a tail clamp. Ability to move was divided into three categories: (a) movement of both hind limbs and a response to tail pinch, (b) movement of one hind limb and a response to tail pinch, and (c) no movement of either hind limb or no response to tail pinch

For a given rat, MAC was calculated as the mean and sd of the isoflurane concentrations that just permitted and just prevented movement. For the tests in which intraperitoneal injections of muscarinic and nicotinic antagonists were made, we applied a paired t-test to compare the MAC values obtained for the test groups with the MAC values obtained in the average of the two control (saline) groups. A Bonferroni correction was applied when multiple study results were obtained in the same group of rats (i.e., we accepted a P value of <0.01 as significant). Similarly, we applied paired t-tests for the change in MAC produced by the intrathecal administration of atropine.

	Results

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The value for the control (saline) MAC obtained at the start of the first MAC studies (1.57% ± 0.11% isoflurane) did not differ from that obtained at the end (1.56% ± 0.11% isoflurane), and the values for these two determinations were averaged for each rat to arrive at the final MAC value used for comparison with each treatment group. No treatment MAC value differed from control (Table 1), although the value for the 2 mg/kg of mecamylamine plus 10 mg/kg of atropine approached significance. Injection of 10 or 100 mg/kg of scopolamine did not significantly change MAC (Table 1), although one rat died after anesthesia and 100 mg/kg of scopolamine. The rat that died had the largest decrease in MAC (14.6%). If that rat is excluded, the change in MAC remains insignificant (1.66% ± 0.12% versus 1.63% ± 0.14%).

View larger version (25K): [in this window] [in a new window]   Figure 1. The intrathecal administration of atropine to groups of four rats did not significantly change isoflurane minimum alveolar anesthetic concentration (MAC) at infusion concentrations that did not produce obvious injury to the spinal cord (the smallest two doses). Larger doses could decrease MAC in association with subsequent injury. The numbers associated with each mean value indicate the numbers of rats contributing to that value.

	Discussion

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We found that block of muscarinic acetylcholine receptors with atropine (given by intraperitoneal or intrathecal administration) or scopolamine and nicotinic acetylcholine receptors with mecamylamine (given by intraperitoneal administration) did not affect the capacity of isoflurane to produce immobility (Table 1, Fig. 1) unless the dose of the antagonist produced permanent nerve damage. Of course we cannot exclude the possibility that a different antagonist might have allowed application of still larger effective doses without injury. Our findings confirm those of Flood et al. (15) who demonstrated that block of neuronal nicotinic receptors with mecamylamine or chlorisondamine in mice did not change isoflurane MAC. They are consistent with the finding that inhaled anesthetics inhibit acetylcholine receptors at concentrations far less than MAC (4) (i.e., if acetylcholine receptors mediated MAC, the in vitro study results would indicate that MAC should be much smaller than it is). In addition, although one report suggests that the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) does not block neuronal nicotinic acetylcholine receptors (16), other preliminary reports find that it does (Douglas Raines, Harvard Medical School, personal communication, 2001) (17), suggesting that nonimmobilizers can inhibit nicotinic acetylcholine receptor. Such inhibition would be inconsistent with a role for such receptors as mediators of the capacity of inhaled anesthetics to produce immobility. Finally, our results are consistent with those of Wong et al. (18) in the spinal cord. Application of muscarinic and nicotinic antagonists did not alter the actions of isoflurane in this isolated preparation.

We gave enormous (0.4–8 mg) intrathecal doses of atropine. These resulted from infusions of 1.25 x 10^-6 to 40 x 10^-6 mg/min into the lumbar region of the spinal cord. If we assume distribution into a volume of 10 µL that was renewed each minute by blood perfusing the cord, we can estimate a concentration bathing the spinal cord of approximately 0.4–12 µmol/L of atropine. Such concentrations of atropine cause block of neuronal nicotinic, as well as muscarinic, acetylcholine receptors (19). If these very rough calculations are correct, they suggest that we measured the effect of spinal block of both nicotinic and muscarinic transmission on MAC. Our finding of no change in MAC by intrathecal atropine infusions that did not cause permanent injury (Fig. 1) is consistent with our finding that intraperitoneal injection of large doses of atropine, scopolamine, and mecamylamine do not change MAC (Table 1). Both sets of experiments indicate that muscarinic and nicotinic receptors do not mediate the capacity of inhaled anesthetics to produce immobility.

We found that intrathecal doses of atropine 4 mg and 8 mg caused cord injury and sometimes death and decreased MAC by 38%–100% (Fig. 1). Similarly, Zebrowska-Lupina et al. (20) found that 500 µg given into the lateral ventricle of the brain in unanesthetized rats caused death in approximately 50% of them. These doses caused increases in movement after transient loss of the righting reflex. They prolonged anesthesia from chloral hydrate but not from hexobarbital.

The increased movement seen be Zebrowska-Lupina et al. (20) may be similar to the movement we saw during intrathecal infusion of larger concentrations of atropine. Such an infusion produced spontaneous movement or movement in response to touching the tail (but not necessarily movement in response to pinching the tail). Activation of muscarinic cholinergic M2 receptors depresses glutamatergic excitatory postsynaptic currents, and atropine blocks this action of acetylcholine (21,22). Acetylcholine probably blocks these excitatory impulses by a presynaptic effect on acetylcholine release (21). Possibly, the toxic effect of large concentrations of intrathecal atropine resulted from suppression of this inhibitory effect of acetylcholine on glutamatergic transmission, producing abnormal movements, cord damage, and death. That is, block of cholinergic transmission can release excitatory pathways from inhibitory restraint, and if this block exceeds the block of excitatory pathways, the resulting excitation can damage neurons (23). We conclude that neither muscarinic nor nicotinic receptors are important to the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation.

	Acknowledgments

 
Supported, in part, by NIH Grant No. 1PO1GM47818-07.

	Footnotes

 
Dr. Eger is a paid consultant to Baxter Healthcare Corp. Baxter donated the isoflurane used in these studies.

	References

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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