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Vol. 293, Issue 3, 845-851, June 2000
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu, Japan
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The brain stem reticular formation plays an important role in determining consciousness and arousal. Modulation of cholinergic neurotransmission in this region alters the sleep-wake cycle. In the present study, we examined the effect of the direct application of cholinergic agents into the pontine reticular nucleus on anesthetic requirements and recovery and antinociception in rats. Sprague-Dawley rats were implanted with 24-gauge guide cannulas 1.0 mm above the oral portion of pontine reticular nucleus (PnO) while under pentobarbital anesthesia with the use of a stereotaxic apparatus. After recovery from surgery, animals were randomly assigned to one of the following protocols: minimum alveolar concentration (MAC), recovery time, tail-flick latency, or motor blockade. All measurements were performed after carbachol microinjection into the PnO after pretreatment with atropine or mecamylamine. Carbachol injection into the PnO significantly reduced MAC of halothane and prolonged recovery in a dose-dependent manner. Pretreatment with atropine reversed MAC reduction by carbachol, and both atropine and mecamylamine shortened recovery time under carbachol. In unanesthetized rats, carbachol produced antinociceptive effects as reflected by a change in tail-flick latency response. Atropine and mecamylamine inhibited antinociceptive effects of carbachol. These results suggest that cholinomimetic injection into the PnO modulates the anesthetic state produced by halothane, suggesting participation of this area in the mechanisms in the brain that generate the anesthetic state.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
brain stem reticular formation has been the target of much research in
attempts to define consciousness and arousal (Meyer, 1970
; Steriade et
al., 1993; Steriade, 1996; Coenen, 1998). Progress in neuroscience in
the past few decades has delineated that the arousal system originates
in the upper brain stem reticular formation and projects to the
cerebral cortex through synaptic relays in the thalamus (Meyer, 1970;
Steriade et al., 1993, 1996; Coenen, 1998). The main neurotransmitters
identified in the brain stem to cortex circuit include acetylcholine,
norepinephrine, serotonin, and glutamate (Steriade et al., 1993;
Steriade, 1996). In addition to generating arousal and different levels
of awareness, the major functions of the reticular formation include
cardiopulmonary control, control of somatic motor tone, and modulation
of pain perception (Role and Kelly, 1991).
Evidence suggests that the state of general anesthesia is generated in
the anatomically distributed neuronal networks ranging from spinal to
cerebral levels (Angel, 1993; Durieux, 1996; Antognini, 1997; Lydic and
Baghdoyan, 1997). A cholinergic network in the brain stem reticular
formation has been demonstrated to play a key role in generating some
of the physiological characteristics observed during general anesthesia
(Morales et al., 1987; Lydic et al., 1991; Keifer et al., 1996). For
example, cholinomimetic injection into the pontine reticular formation
inhibits spinal motoneuron excitability in cats (Morales et al., 1987).
Cholinergic transmission in this region is also known to contribute to
respiratory depression (Lydic et al., 1991). Furthermore, the direct
application of cholinomimetics into the oral portion of pontine
reticular nucleus (PnO) alters sleep-wake cycles and causes an increase in a rapid eye movement (REM) sleep-like state in rats (Gnadt and
Pegram, 1986; Imeri et al., 1994; Bourgin et al., 1995). The blockade
of muscarinic receptors in that region was shown to enhance wakefulness
and decrease REM and slow wave sleep in rats (Imeri et al., 1994).
Although the role of cholinergic neurotransmission in general
anesthesia has long been studied, the effect of cholinergic agents on
minimum alveolar concentration (MAC) has been controversial (Horrigan,
1978; Zucker, 1991; Ishizawa et al., 1997). The i.p. injection of
physostigmine, an acetylcholinesterase inhibitor, decreased halothane
MAC in rats (Ishizawa et al., 1997), but another study showed that
physostigmine increased isoflurane MAC in rats (Zucker, 1991). The
effects of i.c.v. administration of cholinergic agents on MAC also were
not consistent (Zucker, 1991). On the other hand, intrathecally
administered cholinergic agonists are well known to consistently
produce analgesia (Yaksh et al., 1985). Therefore, a study of the roles
of discrete regions in the central nervous system in anesthesia could
provide important information for further understanding cholinergic
contribution to general anesthesia.
The present study was thus designed to detect whether directly administered cholinergic agents in the brain stem reticular formation change the state of anesthesia as well as antinociceptive responses in rats. The hypothesis tested in this study was that halothane requirements and recovery are modulated by microinjection of carbachol in the PnO in rats. We also tested the hypothesis that antinociceptive responses are altered by carbachol injection into the PnO using tail-flick latency in unanesthetized rats.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animals. With approval of the animal care and use committee of our institution, studies were performed on male Sprague-Dawley rats weighing 250 g (8 weeks old). Rats were housed individually in a temperature-controlled (21-24°C) room with a 12-h light/dark cycle, and they were given free access to water and food. All experiments were performed between 10:00 AM and 6:00 PM. A total of 80 animals was used. Each animal was assigned to only one of the following protocols: MAC of halothane (the number of rats; n = 30), recovery time (n = 16), tail-flick latency (n = 20), or motor response (n = 14). Each animal was studied three or four times in the assigned protocol at an interval of 5 days between studies.
All surgical procedures were performed with the rats during anesthesia with 50 mg/kg i.p. pentobarbital. The rat was positioned in a stereotaxic apparatus (Narishige, Tokyo, Japan). A 24-gauge stainless steel guide cannula was unilaterally implanted 1.0 mm above the PnO using the following stereotaxic coordinates: with bregma as reference, 8.7 mm posterior, 1.0 mm lateral, and 6.4 mm ventral from the dura mater (Paxinos and Watson, 1998). Dental cement was applied to the
skull around the guide cannula and around the screws fixed in the
skull. The cannula was kept sealed, except during the injection. After
surgery, the rats were again housed individually and allowed to recover
for 5 days before any of the experiments described in the following
sections. Experiments were carried out over the 4 weeks.
MAC of Halothane.
Anesthesia was induced through inhalation
of halothane in a transparent container (Fig.
1A). The rat's trachea was intubated with a 16-gauge cannula, and the lungs were mechanically ventilated with halothane in oxygen and air (FIO2
0.5, rodent ventilator model 683; Harvard Apparatus, Holliston, MA).
End-tidal carbon dioxide pressure was maintained at 35 to 40 mm Hg.
Rectal temperature was continuously monitored and maintained at
37.5°C with a heating pad. Fifteen minutes after the initiation of
halothane anesthesia, a 30-gauge internal cannula connected to
polyethylene tubing was inserted into the guide cannula and positioned
1.0 mm below the tip. Atropine sulfate at 4.0 µg (19.6 mM) or 12.0 µg (59.0 mM), mecamylamine hydrochloride at 1.0 µg (16.3 mM) or 4.0 µg (65.3 mM), or saline was injected into the PnO in a volume of 0.3 µl over 90 s using a microinjection pump (CMA/100;
Microdialysis, Acton, MA). Carbachol at 5.0 µg (136.9 mM), 10.0 µg
(273.8 mM), or saline was injected into the PnO in a volume of 0.2 µl
over 60 s at 15 min after pretreatment with antagonists or saline.
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). Briefly, the administration of halothane was adjusted in
steps of 0.1%, and a stable end-tidal concentration for 15 min was
obtained before stimulation. Noxious stimulation was applied with a
6-inch hemostat to the middle third of the tail for 60 s at the
first ratchet position. The criteria for positive movements included
purposeful movements of either the head or the four extremities. When
the animal had a positive response, the halothane concentration was
increased; when there was no response, the concentration was decreased
until movement was observed. When the interval was bracketed by
positive and negative responses, the midpoint of the interval was then
tested. The MAC of halothane for each rat was defined as being midway
between the highest end-tidal concentration with a positive response
and the lowest end-tidal concentration with a negative response.
End-tidal gas samples were obtained with an airtight glass syringe
through a 26-gauge needle inserted to a tracheal tube during 15 expirations. Halothane concentrations were analyzed using an infrared
analyzer (M1025B; Hewlett Packard). Calibration with the standard gas
was performed before study. All chemicals were purchased from Sigma
Chemical Co. (St. Louis, MO).
Recovery Time of Halothane Anesthesia. While the rats were loosely restrained in a rodent restrainer (Braintree Scientific Inc., Braintree, MA), atropine sulfate (4.0 µg), mecamylamine hydrochloride (1.0 µg), or saline was injected into the PnO in a volume of 0.3 µl over 45 s (Fig. 1B). Anesthesia was induced by placing the rats in the airtight transparent container flowed with 2% halothane in air at 3 l/min through insufflating and draining tubes connected to the container. Fifteen minutes after the initiation of anesthesia, the rats were withdrawn from the anesthetic and carbachol (1.0 or 5.0 µg) or saline was immediately injected in a volume of 0.2 µl over 30 s into the PnO. The rats were promptly placed on their backs on the heating table at 30°C. As soon as they turned over so that all four feet contacted the surface, they were placed on their backs again. The second performance of this righting reflex was recorded, and the recovery time was defined as the time between withdrawal of halothane and the second performance of the righting reflex. The rate of breathing was measured during halothane anesthesia and the recovery.
Antinociceptive Testing.
Nociceptive threshold was assessed
using tail-flick latency test (Fig. 1C). A noxious somatic stimulus was
measured by monitoring the latency to withdrawal from a high-intensity
light focused on the dorsal surface of the tail (Thermal Analgesimeter
model KN-205E; Natume, Tokyo, Japan). A cutoff time of 10 s
was predetermined to minimize the risk of tissue damage. After baseline
measurements for tail-flick latency had been obtained, each animal
received atropine sulfate (4.0 µg), mecamylamine hydrochloride (1.0 µg), or saline injection into the PnO in a volume of 0.3 µl over
90 s. Fifteen minutes after the pretreatment, carbachol (1.0 or
5.0 µg) or saline was injected into the PnO, and tail-flick latencies were determined 5, 10, 15, 20, 30, 40, 50, and 60 min after
microinjection of carbachol or saline. Data are expressed as maximum
possible effect (MPE) according to the following formula: MPE (%) = [(postdrug latency) 
(basal latency)/(cutoff latency) (basal latency)] × 100.
) as follows: 0 indicates free movement of
hindlimbs without limitation; 1, limited or asymmetrical movement of
the hindlimbs to support the body and walk; 2, inability to support the
back of the body on the hindlimbs, with detectable ability to move the
limbs; and 3, total paralysis of the hindlimbs. When righting reflex
was impaired in the rats, motor blockade was not graded because limb
paralysis was difficult to evaluate properly.
Histological Localization of PnO Microinjection Sites.
On
completion of the experiments, animals were deeply anesthetized with
pentobarbital, and 1.0 µl of 2.5% bromophenol blue was injected at
the stereotaxic target. After euthanasia with an overdose of
pentobarbital, the brains were immediately soak-fixed in 10% neutral
formaldehyde. The brains were serially sectioned into 0.3- to 0.5-mm
coronal slices. The microinjection sites were histologically localized
with the use of the atlas of Paxinos and Watson (1998). Furthermore,
the sections that contained injection sites were embedded in paraffin
and sectioned at 20-µm thickness. The sections were stained with
Luxol fast blue. The target area was defined as the area of the PnO at
the level between 8.3 and 8.8 mm posterior from the bregma.
Statistical Analysis.
Data are presented as mean ± S.E. Differences in MAC and recovery time were compared using ANOVA.
Tail-flick latency data were compared by two-way ANOVA for repeated
measurements. Comparisons of motor blockade and righting reflex data
were performed at each time point by 
2 test.
The Student-Neuman-Keuls procedure or Bonferroni's correction was used
for post hoc comparisons. Probability levels of <.05 were considered significant.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The region where drugs were microinjected in the PnO is shown in
Fig. 2. A typical microinjection site is
shown in Fig. 2A, and a schematic drawing shows microinjection sites in
the rats studied in the two representative coronal sections of rat
brain stem (Fig. 2B).
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The effects of carbachol and antagonist pretreatment on MAC are
illustrated in Fig. 3. MAC of halothane
was significantly reduced by direct application of carbachol into the
PnO in a dose-dependent manner. MAC of halothane in the control group
(saline injection after saline pretreatment) was 0.95 ± 0.05%,
which is in a good agreement with previously reported MAC values (White
et al., 1974; Ishizawa et al., 1997). Carbachol at 5.0 and 10.0 µg
with saline pretreatment decreased MAC of halothane by 29 and 52%,
respectively. Pretreatment with 4.0 and 12.0 µg atropine inhibited
MAC reduction by 5.0 µg carbachol. Atropine at 12.0 µg inhibited
the effect of 10.0 µg carbachol, but atropine at 4.0 µg did not,
suggesting a dose-dependent inhibitory effect of atropine. Mecamylamine
did not cause significant changes in the effects of carbachol on MAC.
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The effects of carbachol and antagonist pretreatment on the recovery
time from halothane are illustrated in Fig.
4. Carbachol at 1.0 and 5.0 µg
microinjected into the PnO significantly prolonged recovery time in a
dose-dependent manner. Pretreatment with 4.0 µg of atropine or 1.0 µg of mecamylamine significantly reduced prolonged recovery time by
carbachol. Mean respiratory rates during anesthesia and recovery and
the number of total breaths taken to recover are shown in Table
1. Neither preinjected atropine nor
mecamylamine showed significant effects on the respiratory rates during
halothane anesthesia. During recovery, the groups of saline with
atropine pretreatment and saline with mecamylamine pretreatment showed
significantly higher respiratory rates than carbachol with saline
pretreatment. Carbachol significantly increased the number of total
breaths taken to recover in a dose-dependent manner.
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Figure 5 shows the time course of the
tail-flick latency change. Carbachol at 1.0 and 5.0 µg microinjected
into the PnO significantly prolonged tail-flick latency. The maximum
increase in tail-flick latency, expressed as MPE, occurred within 5 min
of the administration of carbachol. The effect of 1.0 µg of carbachol
was significant for 30 min after injection, and 5.0 µg of carbachol
showed a significant effect over 60 min after injection. Tail-flick
latency was significantly higher in the rats administered 5.0 µg of
carbachol than 1.0 µg at 30, 40, 50, and 60 min, suggesting a
dose-dependent effect of carbachol. Pretreatment with 4.0 µg of
atropine or 1.0 µg of mecamylamine inhibited tail-flick latency
prolongation by carbachol. Figure 6
summarizes the effects of carbachol and its antagonists on motor
blockade and righting reflex in unanesthetized rats. A small number of
the rats administered 1.0 or 5.0 µg of carbachol showed loss of
righting reflex or mild motor impairment. All motor impairments
observed were graded 1 (limited or asymmetrical movement of the
hindlimbs to support the body and walk). In general, there is no
statistically significant relationship between nine different conditions and whether either motor function or righting reflex was
impaired. Most of these effects became undetectable within 30 min after
injection. Except as described above, the behavior of the rats was
unremarkable.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Cholinergic Mechanisms in Brain Stem and General Anesthesia. The present data demonstrate that cholinomimetic injection into the pontine reticular formation modulates halothane anesthesia through cholinergic mechanisms. Directly administered carbachol into the PnO markedly reduced anesthetic requirements of halothane through a muscarinic receptor-mediated mechanism. Recovery time from halothane anesthesia was also prolonged by carbachol injection into the PnO. The effect was inhibited by both muscarinic and nicotinic antagonists. Because carbachol also caused significant increases in the number of total breaths taken to recover along with prolongation of the recovery time, pharmacokinetic explanation are unlikely to explain the prolonged recovery by carbachol. These results thus suggest that cholinomimetic injection into the PnO facilitates the cholinergic mechanisms in the brain that contribute to the anesthetic state.
Cholinergic modulation of anesthesia has been extensively studied in the past decades (Durieux, 1996). However, the findings, particularly
those of cholinergic effects on MAC, have been controversial. The
i.c.v. injection of atropine did not alter MAC of isoflurane, but the
i.c.v. injection of pancuronium decreased MAC in rats (Zucker,
1991). The i.c.v. injection of nicotine showed a biphasic effect on
MAC, increasing it at a low concentration and decreasing it at a high
concentration (Zucker, 1991). Furthermore, physostigmine, an
acetylcholinesterase inhibitor, has been considered to decrease the
depth of anesthesia by increasing brain acetylcholine (Saelens et al.,
1973; Romano and Shih, 1983). However, systemic administration of
physostigmine decreased halothane MAC in rats but induced waking patterns on electroencephalography at the same time (Ishizawa et al.,
1997). Physostigmine was shown to increase isoflurane MAC in rats in
another study (Zucker, 1991). The explanation of these inconsistencies
is not clear. However, most of these studies did not use
pharmacological blocking experiments with selective antagonists. In
addition, cholinergic agents such as physostigmine show dose-dependent
changes in their action at multiple sites (Pleuvry and Tobias, 1971;
Schultz et al., 1993), and thus the effects of physostigmine observed
in these previous studies may not occur only through cholinergic
mechanisms. Finally, it might be possible that cholinergic effects on
anesthesia will vary depending on the anesthetic drug per se.
In the present study, atropine, a nonselective muscarinic antagonist,
inhibited the effects of carbachol on MAC and those on recovery time.
This is consistent with the previous reports that showed muscarinic
receptors play an important role in determining the level of
consciousness (Fibiger, 1991; Durieux, 1996). In particular, muscarinic
receptors in the PnO play a key role in sleep and wake states (Imeri et
al., 1994). The microinjection of the selective
M2 antagonist methoctramine into the PnO enhanced wakefulness and decreased REM sleep and slow wave sleep, but
M1 or M3 antagonists had no
effect on sleep-wake cycles in rats (Imeri et al., 1994). Carbachol
microinjection was further shown to activate G proteins through
muscarinic receptors in the PnO (Capece et al., 1998). Autoradiographic
studies have confirmed the localization of M1,
M2, and M3 subtypes in the
pontine reticular formation in rats (Baghdoyan, 1997). In fact, the PnO
is a cholinoceptive area and has been demonstrated to receive
cholinergic projections from the laterodorsal tegmental nucleus (LDT)
and pedunculopontine tegmental nucleus (PPT) in the brain stem (Semba
et al., 1990; Semba, 1993). On the other hand, the functional
significance of nicotinic receptors in the brain stem arousal system is
less well defined. Nicotine microinjected in the pontine reticular
formation was reported to increase REM sleep in cats
(Velazquez-Moctezuma et al., 1990). The expression of
4 and 
2 nicotinic
acetylcholine receptor subunits have been demonstrated in the PnO in
rats (Wada et al., 1989), which gives a neuroanatomical basis for the
present finding that mecamylamine inhibited the effect of carbachol on recovery time. The present results may suggest that neuronal nicotinic receptors in the PnO also play a role in the state of general anesthesia.
The present study was designed to address the effects of directly
administered cholinergic agents in the PnO on halothane anesthesia and
to confirm the effects were cholinergically mediated in the PnO.
However, the present study was not designed to show whether cholinergic
agents directly interact with halothane within the PnO. It is well
understood that cholinergic neurons in the brain stem project to the
thalamus and higher structures and receive sensory afferent input from
the spinal cord (Role and Kelly, 1991; Durieux, 1996). In fact,
cholinergic neurons in the LDT/PPT have been demonstrated to have
simultaneous projections to the thalamus and to the PnO in rats (Semba
et al., 1990), suggesting that the effect of cholinomimetic injection
in the PnO could have direct influence on neurons in the thalamus.
Furthermore, the brain stem reticular formation is a complex of
distinct as well as interacting neuronal regions (Role and Kelly, 1991;
Steriade et al., 1993; Steriade, 1996; Coenen, 1998). The PnO receives
various inputs from these reticular neurons, including noradrenergic
afferents from the locus ceruleus and serotoninergic afferents from the raphe nuclei (Semba, 1993). The LDT/PPT cholinergic neurons also project to the locus ceruleus and the raphe nuclei (Semba and Fibiger,
1992). These neuroanatomical findings suggest that cholinergic, serotoninergic, and noradrenergic inputs may act convergently on the
neurons in the PnO. Therefore, modulation of halothane anesthesia
observed in the present study might be the consequence of interactions
of cholinomimetic injection with halothane at any level of the
cholinergic network in the central nervous system.
Cholinergic Modulation of Antinociception.
Carbachol
microinjected into the PnO induced significant and consistent
prolongation of tail-flick latency in unanesthetized rats. This effect
was nearly completely abolished by pretreatment with atropine or
mecamylamine. Although many reticular neurons in the brain stem are
known to respond preferentially to noxious stimuli and the reticular
formation receives afferent input through the spinoreticular tract
(Willis and Westlund, 1997), neurotransmitters involved in these
neuronal pathways and possible neuronal connections in the brain stem
are not well understood. However, the present results confirmed that
the antinociceptive effect of carbachol injection into the PnO was
cholinergically mediated. A recent study also showed that
cholinomimetics injected into the pontine reticular formation in cats
increased tail-flick latency (Kshatri et al., 1998). These data
together strongly suggest that the pontine reticular formation plays a
role in supraspinal antinociceptive behavior. Nicotine was previously
reported to produce antinociception through both presynaptic nicotinic
and postsynaptic muscarinic receptors in the PPT in rats (Iwamoto,
1989). Because cholinergic neurons in the PPT project to the PnO,
carbachol injection into the PnO could elicit the same mechanism of
antinociception as nicotine in the PPT.
Limitations and Conclusions.
In the present study, both
muscarinic and nicotinic antagonists inhibited the effects of carbachol
on recovery time as well as on antinociception. However, only the
muscarinic antagonist showed reversal of MAC reduction caused by
carbachol. The explanation of these inconsistencies is not clear but
might be due to pharmacokinetic differences at the injection site
between the antagonists. In addition, the duration of various effects
elicited by carbachol injection into the PnO varied. Carbachol
(0.1-5.0 µg) was reported to cause an increase in REM sleep over
several hours after the injection (Bourgin et al., 1995). On the other
hand, its antinociceptive effect was sustained for 30 to 60 min in the
present study. These data may suggest that the extensiveness of the
neuronal connections involved in these responses, such as MAC and
tail-flick latency, could be different and may contribute to the
difference in the pharmacological blocking effects observed in the
present study.
). However, increased understanding of the complexity of the state
of general anesthesia has made the concept of MAC considerably more
difficult to apply. In fact, the measurements of MAC, particularly MAC
reduction, without an attempt to differentiate effects on
consciousness, nociception, and motor function might be better to be
considered incomplete. The present results, including nociception and
motor function data, have clearly shown that cholinomimetic injection
into the pontine reticular formation reduced anesthetic requirements
and produced antinociception in rats, suggesting that cholinomimetics
in the PnO modulate the mechanisms in the brain that generate
anesthetic state and antinociception.
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Acknowledgments |
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We thank Dr. Roderic G. Eckenhoff for helpful discussion.
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Footnotes |
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Accepted for publication March 3, 2000.
Received for publication January 7, 2000.
1 This work was supported by the Department of Anesthesiology and Critical Care Medicine (Gifu University School of Medicine, Gifu, Japan) and by Grant A-100770748 from the Ministry of Education, Japan (to Y.I.).
Send reprint requests to: Dr. Yumiko Ishizawa, Department of Anesthesia, University of Pennsylvania Medical Center, 3400 Spruce St., 7 Dulles, Philadelphia, PA 19104-4283. E-mail: ishizawa{at}mail.med.upenn.edu
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Abbreviations |
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PnO, oral portion of pontine reticular nucleus; MAC, minimum alveolar concentration; REM, rapid eye movement; MPE, maximum possible effect; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; LC, locus ceruleus.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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P < .05 versus 5.0 µg of carbachol
with saline pretreatment. 
P < .05 versus 10.0 µg of carbachol with saline pretreatment (all one-way
ANOVA followed by Student-Neuman-Keuls test).
, saline + saline; 
,
saline + carb 1.0; 
, saline + carb 5.0; 
, atropine + saline; 
,
atropine + carb 1.0; 
, atropine + carb 5.0; 
, mecamyl + saline;
, mecamyl + carb 1.0; 
, mecamyl + carb 5.0.
, motor blockade grade 1;