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Anesth Analg 2002;94:1201-1206
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Alpha-2 Adrenoceptor Activity Affects Propofol-Induced Sleep Time

Tetsuya Kushikata, MD, Kazuyoshi Hirota, MD, Hitoshi Yoshida, MD, Takeshi Kubota, MD, Hironori Ishihara, MD, and Akitomo Matsuki, MD

Department of Anesthesiology, University of Hirosaki School of Medicine, Japan

Address correspondence and reprint requests to Tetsuya Kushikata, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, 5 Zaifu-cho, Hirosaki, Japan. Address e-mail to tkush{at}df6.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
{alpha}2 Adrenoceptor activity is involved in the mechanism of anesthesia. Clonidine, a {alpha}2 adrenoceptor agonist, and yohimbine, a {alpha}2 adrenoceptor antagonist, increase and decrease barbiturate-induced sleep times. In this study, we examined the effects of these drugs on propofol-induced sleep time. One-hundred-eighteen male Wistar rats weighing 320–400 g were used. Rats received saline, yohimbine (1, 0.1, or 0 mg/kg), or clonidine (300, 30, 3, or 0 µg/kg) intraperitoneally followed by 60 mg/kg of propofol in various combinations. In two series of experiments, either sleep time or prefrontal cortex norepinephrine release (microdialysis) was measured. One milligram/kilogram of yohimbine decreased propofol-induced sleep time to approximately 70% of control, and this was accompanied by an increase in perfusate norepinephrine of approximately 240% of control. Clonidine increased sleep time approximately 260% (300 µg/kg) and approximately 170% (30 µg/kg), and this was accompanied by a decrease (approximately 60% in both doses) in perfusate norepinephrine. In the present study, we show that the {alpha}2 antagonist, yohimbine, decreased and the {alpha}2 agonist, clonidine, increased propofol-induced sleep times. These changes were essentially mirrored in both groups by changes in norepinephrine release in the prefrontal cortex.

IMPLICATIONS: Central {alpha}2 adrenoceptor is thought to be involved in several IV anesthetics-induced sleep. In this study, activation of the receptor increased the propofol-induced sleep time, whereas its inhibition decreased the sleep time. The results provide further evidence that the {alpha}2 receptor is a good tool to elucidate the mechanism of anesthetics-induced sleep.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Several lines of evidence suggest that {alpha}2 adrenoceptor activity is involved in the mechanism of anesthesia-induced sleep time. For example, the {alpha}2 adrenoceptor agonist, clonidine, increased and the {alpha}2 adrenoceptor antagonist, yohimbine, decreased barbiturate-induced sleep times (1). Moreover, depletion of brain norepinephrinergic neurons with 6-hydroxydopamine increases sleep time (2). In addition, modulation of central nervous system (CNS) norepinephrinergic activity by several antidepressants also affects sleep times (3).

Using microdialysis, we previously reported that several general anesthetics modulate brain norepinephrine release in rats. For example, ketamine increased norepinephrine release from the prefrontal cortex, whereas pentobarbital and midazolam produced a decrease (4–6). In addition, norepinephrine release is increased in the posterior hypothalamus during emergence from sevoflurane or halothane anesthesia (7). Collectively, these data indicate that changes in brain norepinephrinergic neuronal activity may be of importance in the process of general anesthesia. Alpha-2 adrenoceptor control of norepinephrinergic neuronal activity may also be involved in the modulation of sleep (1,8).

The often used general anesthetic, propofol, decreases norepinephrine release from the prefrontal cortex of the rat (5), and 6-hydroxydopamine depletion also prolongs propofol-induced sleep time (9). Therefore, we hypothesized that {alpha}2 adrenoceptor activity may also contribute to propofol-induced sleep time.

In this study, we examined whether stimulation or inhibition of central {alpha}2 adrenoceptor activity, which would decrease or increase norepinephrine, respectively, affects propofol-induced sleep times. In addition, we made direct measurements of norepinephrine release from the prefrontal cortex using a microdialysis technique.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Yohimbine hydrochloride (a {alpha}2 antagonist), clonidine hydrochloride (a {alpha}2 agonist), and dimethyl sulfoxide (DMSO) were purchased from Wako Pure Chemical Industries, Ltd (Osaka, Japan). Pyrogen free physiologic saline (PFS) was purchased from Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan).

With approval from the institutional committee on animal research of the University of Hirosaki School of Medicine (Hirosaki, Japan), a total of 118 male Wistar rats (320–400 g; Japan Clea, Kyoto, Japan) were used (n = 76 for Experiment 1 and n = 42 for Experiment 2). For at least 1 wk before the experiment, all rats were housed on a 12 h light/dark cycle (lights on from 8:00 AM to 8:00 PM) at a temperature of 22°C–24°C and 40% humidity. Rats were allowed access to food and water ad libitum except on the day of the experiment. All experiments were performed between the hours of 11:00 AM and 3:00 PM to control for the diurnal rhythm of norepinephrinergic neuronal activity.

Experiment 1: Effect of Yohimbine and Clonidine on Propofol-Induced Sleep Times
In the Yohimbine group, control animals received 10% DMSO in 0.3 mL of PFS intraperitoneally, and 60 min later, propofol 60 mg/kg was injected intraperitoneally. Three to four days later, the same rats then received either yohimbine (made in 10% DMSO) 0, 0.1, or 1.0 mg/kg (n = 12 per dose) intraperitoneally. The same dose of propofol was injected 60 min later. In the Clonidine group, control animals received 0.3 mL of PFS intraperitoneally. Three to four days later, the same rats then received either clonidine 0, 3, 30, or 300 µg/kg (n = 10 per dose) intraperitoneally. Propofol was then administered 60 min later as above.

The induction time of propofol anesthesia was defined as the duration from injection of propofol to loss of three successive righting reflexes. Anesthesia-induced sleep time was defined as the duration from the loss of the righting reflex to recovery of the ability to perform three successive rightings.

Experiment 2: Effect of Yohimbine and Clonidine on Norepinephrine Release from the Rat Prefrontal Cortex
Rats were mounted onto a stereotactic frame (David-KopfTM brain fixation device, No. 30–1000, BAS, Tokyo, Japan) under pentobarbital anesthesia (50 mg/kg intraperitoneally). A stainless-steel guide cannula (outer diameter = 0.5 mm; AG-4, EICOM, Kyoto, Japan) was implanted unilaterally into the medial prefrontal cortex using the following stereotactic coordinates (AP: 3.3 mm, L: 0.4 mm, V: 2.0 mm) according to the atlas of Watson and Paxinos (10). The cannula was fixed to the skull surface with dental cement (QUICK RESINTM, Shofu, Kyoto, Japan) and with two stainless-steel screws that were inserted above the cerebral cortex. Twenty-four hours after guide cannula implantation, a microdialysis probe (outer diameter = 0.22 mm; A-I-4–03, EICOM, Kyoto, Japan) with 3 mm of semipermeable membrane in its tip was inserted via the cannula. The tip of the probe protruded 3 mm from the tip of the guide cannula. At the end of the experiment, probe location was histologically verified.

Twenty-four hours after probe insertion, the rat was moved into a custom built plastic box where it could move freely (Free moving unitTM CMA/125, BAS, Tokyo, Japan). The probe was then perfused at a flow rate of 1.3 µL/min with artificial cerebrospinal fluid with the following composition (mmol/L): NaCl (128), KCl (2.6), CaCl2 (1.3), MgCl2 (0.9), NaHCO3 (20), Na2HPO4 (1.3), containing 1 mmol/L of pargyline, a monoamine oxidase inhibitor, which was included to prevent degradation of norepinephrine. After an equilibration period of 120 min, dialysates were collected at 10-min intervals. After obtaining 6 consecutive samples for baseline, yohimbine or clonidine was injected intraperitoneally, and 60 min later, propofol 60 mg/kg was administered intraperitoneally. Three doses of yohimbine (0, 0.1, and 1.0 mg/kg; n = 6 per dose) and four doses of clonidine (0, 3, 30, and 300 µg/kg; n = 6 per dose) were studied.

Measurement of Dialysate Norepinephrine Contents
Norepinephrine, in 10 µL dialysate samples, was measured by high-pressure liquid chromatography with electrochemical detection (graphite electrode, ECD-300, EICOM, Kyoto, Japan, set at +400 mV against a Ag/AgCl reference electrode). Norepinephrine was separated on an ODS-C18 column (ø 2.1 x 150 mm, CA-50 DS, EICOM, Kyoto, Japan) maintained at 25°C with a mobile phase of 0.1 mol/L phosphate buffer (pH 6.0) containing EDTA 200 mg/L, 1-octanesulphonate 400 mg/L, and 5% methanol at a flow rate of 220 µL/min. The detection limit of the assay was 125 fg/10 µL (signal/noise ratio >3).

Data are expressed as mean ± SEM. Induction and anesthesia-induced sleep time data of each drug per dose were compared with its corresponding control group using the Student’s paired t-test. Data from each drug group were analyzed by repeated measures analysis of variance followed by Fisher’s protected least significant difference test. The area under the curve (AUC) of the norepinephrine concentration time course from 0 to 120 min after yohimbine or clonidine injection were measured with computer based software as in our previous study (11) and analyzed by repeated measures analysis of variance followed by Fisher’s protected least significant difference test. A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1: Effect of Yohimbine and Clonidine on Propofol-Induced Sleep Times
Control propofol-induced sleep times in the Yohimbine and Clonidine groups were 22.6 ± 5.4 min and 23.5 ± 6.9 min, respectively. These values were not significantly different. One mg/kg of yohimbine significantly decreased propofol-induced sleep time to approximately 70% (P < 0.05), whereas clonidine produced a significant increase (300 µg/kg: approximately 260%; 30 µg/kg: approximately 170%, P < 0.01). Control induction time of propofol anesthesia was 6.8 ± 1.0 min and 6.3 ± 1.3 min in the Yohimbine and Clonidine groups, respectively. There was no significant difference between these values, which were unaffected by either yohimbine or clonidine (Fig. 1, A and B, Table 1).



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  		Figure 1. Effect of {alpha}2 adrenoceptor activity on propofol-induced sleep time. Yohimbine decreases, A, and clonidine, B, increases propofol-induced sleep time in rats. Dose = 0 is control. Yohimbine 1.0 mg/kg decreased (*P < 0.05) and clonidine 30 and 300 µg/kg increased the sleep time (*P < 0.01) compared with the appropriate control.

 

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  		Table 1. Effect of Yohimbine and Clonidine on Propofol-Induced Sleep Time
 
Experiment 2: Effect of Yohimbine and Clonidine on Norepinephrine Release from the Prefrontal Cortex
Basal norepinephrine release (-40 to 0 min) in the three Yohimbine groups were similar (Control, 0.77 ± 0.05 mg per sample; Yohimbine 0.1 mg/kg, 0.83 ± 0.02 mg per sample; Yohimbine 1.0 mg/kg, 0.99 ± 0.09 mg per sample). Propofol alone produced a gradual but small decrease in release. Yohimbine (1.0 mg/kg) increased norepinephrine release that peaked 60 min after the administration then remained stable until sampling ended. The AUC of the norepinephrine concentration time course from 0 to 120 min after 1.0 mg/kg was significantly increased to approximately 240% (Control, 10,926%/min ± 362%/min; Yohimbine 0.1 mg/kg, 11,428%/min ± 351%/min; Yohimbine 1.0 mg/kg, 24,196%/min ± 6433%/min) (Fig. 2, A and B).



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  		Figure 2. Effects of intraperitoneal yohimbine on norepinephrine release from the rat prefrontal cortex. In panel A, data are expressed relative to the mean of three samples before the yohimbine administration. In panel A, it can be clearly seen that yohimbine 1.0 mg/kg markedly increased release. In panel B, area under the curve (AUC0–120) is displayed. *P < 0.05 compared with control.

 
Basal norepinephrine release (-40 to 0 min) in the Clonidine groups was also similar (Control, 0.77 ± 0.05 pg per sample; Clonidine 3 µg/kg, 0.83 ± 0.03 pg per sample; Clonidine 30 µg/kg, 0.74 ± 0.09 pg per sample; Clonidine 300 µg/kg, 0.77 ± 0.10 pg per sample). Clonidine (30 and 300 µg/kg) decreased norepinephrine release, with an apparent maximum inhibition occurring at approximately 100 min. The AUC of the norepinephrine concentration time course from 0 to 120 min after clonidine 30 or 300 µg/kg significantly decreased to approximately 60% of control (Control, 10,936%/min ± 358%/min; Clonidine 3 µg/kg, 9965%/min ± 724%/min; Clonidine 30 µg/kg, 6452%/min ± 1234%/min; Clonidine 300 µg/kg, 6357%/min ± 1398%/min) (Fig. 3, A and B).



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  		Figure 3. Effects of intraperitoneal clonidine on norepinephrine release from the rat prefrontal cortex. In panel A, data are expressed relative to the mean of four samples before the clonidine administration. In panel A, it can be clearly seen that clonidine 30 and 300 µg/kg markedly decreased release. In panel B, area under the curve (AUC0–120) is displayed. *P < 0.05 compared with control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this behavioral/microdialysis study, we have shown that yohimbine decreased propofol-induced sleep time, and this was accompanied by an increase in perfusate norepinephrine concentrations. Conversely, clonidine increased sleep time, and this was accompanied by a decrease in perfusate norepinephrine concentrations.

Neurotransmitter release can be modulated via presynaptic autoreceptors that are activated by the neuron’s own transmitter. Presynaptic inhibitory autoreceptors on norepinephrinergic neurons are {alpha}2 that have activation by norepinephrine or exogenous agonists, like clonidine, inhibit release. Conversely inhibition of these receptors by antagonists, such as yohimbine, block the effect of the agonists and may enhance release (12).

The {alpha}2 adrenoceptors are subclassified into {alpha}2A, {alpha}2B, and {alpha}2C, and these share many common properties. All are G-protein-coupled, inhibit adenylate cyclase, inhibit the opening of voltage-gated Ca2+ channels, and enhance the opening of K+ channels (13). In the brain, the {alpha}2A and {alpha}2C subtypes predominate (14). Recent studies have shown that most of the classical {alpha}2 adrenoceptor actions, such as hypotension, sedation, analgesia, hypothermia, and anesthetic-sparing effects, are mediated primarily by {alpha}2A. The {alpha}2C may be responsible for many CNS processes, such as the startle reflex, stress response, and locomotion (15). Therefore, the {alpha}2A adrenoceptor represents a possible anesthetic target. Currently available highly selective {alpha}2 adrenoceptor ligands (agonists: dexmedetomidine, or clonidine; antagonists: atipamezole and idazoxan) have marginal {alpha}2-subtype selectivity (16). Importantly, clonidine and yohimbine are 39- (17) and 680- (18) fold {alpha}2A selective (compared with {alpha}1).

Several lines of evidence suggest that clonidine and yohimbine affect anesthetic-induced sleep times. For example, clonidine increased thiopental induced-sleep time, whereas yohimbine produced a decrease in rats (1). As a logical extension of this study, we hypothesized that these drugs could modulate propofol-induced sleep times. Indeed this was observed with clonidine increasing and yohimbine decreasing propofol sleep times. The dose required for the modulation was similar to previous studies (1,6). The effect of these drugs on the norepinephrine release has a time lag. In clonidine, the effect reached a plateau 60 minutes after the drug administration. In yohimbine, it was also about 60 minutes from our preliminary study (data not shown), thus we administered propofol 60 minutes after these two drugs were given.

In the Control, Yohimbine, and Clonidine groups, norepinephrine release after propofol injection decreased gradually, and this finding is consistent with those from our previous study (5). The underlying mechanism of this decrease in norepinephrine release from the rat prefrontal cortex is unclear. Propofol has a minor effect on the binding of the specific {alpha}2 adrenoceptor agonist, paraiodoclonidine, at cerebral {alpha}2 receptors, (19) thus, direct action of propofol on the {alpha}2 adrenoceptor is unlikely. This inhibition likely results from a yet undefined interaction with a more complex neuronal network.

Norepinephrinergic neurons in the prefrontal cortex exclusively receive innervation from the locus coeruleus (LC), a major center of norepinephrinergic neuronal activity (20), and hence, changes in norepinephrine release in the prefrontal cortex reflect activity in the LC. We show that clonidine decreases, whereas yohimbine increases, prefrontal cortex norepinephrine release. Thus, clonidine may decrease and yohimbine increase LC activity. This is consistent with a previous report showing that the {alpha}2 agonist, dexmedetomidine, decreased LC firing rate in an atipamezole sensitive manner (21). The effect of clonidine 30 µg/kg and 300 µg/kg on norepinephrine release from the rat prefrontal cortex after the propofol administration was similar despite these doses producing discrete effects on propofol-induced sleep time. This discrepancy may be based on detection limits of our high-pressure liquid chromatography assay or on interaction among norepinephrinergic neuron and more complex neuronal network.

In this study, we showed that modulation of {alpha}2 adrenoceptor activity influences propofol-induced sleep time in rats. This is consistent with a previous study where the {alpha}2 antagonist, atipamezole, shortened the recovery time from propofol anesthesia when combined with a {alpha}2 agonist, medetomidine, in rabbits (22). Moreover, data suggest that brain norepinephrinergic neuronal activity may be responsible for propofol-induced sleep in a range of species. Data in humans are lacking.

As propofol enhances {gamma}-amino-butyric acid (GABA)ergic neurotransmission (23), and modulation of GABAergic neuronal activity affects propofol-induced sleep time in mice (24), GABAergic neurons are believed to be involved in the mechanism of propofol-induced sleep. Interestingly, clonidine enhances GABA release from various rat brain regions (25), and conversely, yohimbine inhibits this release (26). In addition, norepinephrine itself increases GABA release from the rat hippocampus (27). This GABAergic-norepinephrinergic interaction may have contributed to changes in propofol-induced sleep times in this study, although the precise mechanisms are unknown. Further studies in this area are clearly warranted.

The induction time in both groups was not different from the Control, although it tended to decrease in the Clonidine group. Although the precise mechanism why anesthetic induction time for propofol did not differ in the two groups remained unclear, it may be suggested that a different mechanism is responsible for the induction of propofol from the mechanism for recovery.

In conclusion, the present study has shown that the {alpha}2 antagonist, yohimbine, decreased, whereas the {alpha}2 agonist, clonidine, increased propofol sleep time in the rat. These changes are accompanied by changes in norepinephrine release in the prefrontal cortex. Our results indicate that CNS norepinephrinergic neuronal activity may be responsible for propofol-induced sleep.


   Acknowledgments
 
Supported, in part, by grant-in-aid 09470323 from the Ministry of Education, Science and Culture, Tokyo, Japan.

We thank David G. Lambert, MD, lecturer in the Department of Pharmacology and Anesthesia, Leicester Royal Infirmary, UK, for his scientific advice on this manuscript.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication December 19, 2001.




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E. I Eger II, Y. Xing, M. J. Laster, and J. M. Sonner
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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