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NEUROPHARMACOLOGY
Department of Pharmaceutical Sciences, College of Pharmacy (M.I., R.M.Q.) and Center for Integrative Biotechnology (R.M.Q.), Washington State University, Pullman, Washington; and Pharmacological Research Section (M.I.), Central Research Labs., SSP CO., LTD., Chiba, Japan
Received February 11, 2003; accepted April 18, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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),
production of conscious sedation for dental surgery in anxious patients
(Jackson and Johnson, 2002),
and emergency relief of severe anxiety and pain
(Kennedy and Luhmann, 2001).
N2O has also been used for patient-administered analgesia
(Castera et al., 2001), relief
of labor pains (Rosen, 2002),
pre-emptive analgesia (Katz,
1995), and reduction of pain and discomfort in various medical
procedures, including intra-articular drug injection
(Cleary et al., 2002),
peripheral intravenous cannulation
(Gerhardt et al., 2001),
sigmoidoscopy (Harding and Gibson,
2000), colonoscopy (Forbes and
Collins, 2000), ophthalmologic procedures
(Cook et al., 2002), and biopsy
procedures (Masood et al.,
2002).
An involvement of endogenous opioid systems in N2O-induced
analgesia is evidenced by observations that N2O antinociception in
experimental animals was sensitive to antagonism by naloxone and other opioid
receptor blockers (Berkowitz et al.,
1976; Quock et al.,
1990,
1993). There is also evidence
that N2O antinociception is secondary to stimulated neuronal
release of endogenous opioid peptides
(Quock et al., 1985; Zuniga et
al., 1987).
Previous studies in our laboratory using the mouse abdominal constriction
model have demonstrated that N2O antinociception was antagonized in
a dose-related fashion by naloxone (Quock
et al., 1993) and, more specifically, by selective 
-opioid
receptor blockers (Quock et al.,
1990). This was also verified by the failure of
-chlornaltrexamine to antagonize N2O antinociception in mice,
in which -opioid receptors were protected against alkylation by
coadministration of a -opioid ligand
(Quock and Mueller, 1991).
This implication of -opioid receptors is also consistent with recent
reports that N2O antinociception in mice is antagonized by i.c.v.
and i.t. pretreatment with rabbit antisera against rat dynorphin
(Branda et al., 2000;
Cahill et al., 2000).
Previous findings from our laboratory also demonstrated that inhibition of
NO synthesis antagonized N2O antinociception in rats and mice
(McDonald et al., 1994). NOS
inhibitors also attenuated the ability of i.c.v. administered -endorphin
to stimulate the neuronal release of methionine-enkephalin in the rat spinal
cord (Hara et al., 1995),
suggesting that stimulated neuronal release of endogenous opioid peptides
might be dependent on NO.
NO is synthesized as a by-product of conversion of its physiological
precursor L-arginine to L-citrulline. This reaction is
catalyzed by a family of enzymes known as NO synthase (NOS). There are two
constitutive forms of the enzyme—neuronal NOS (nNOS) and endothelial NOS
(eNOS)– and an inducible form, inducible NOS (iNOS). nNOS is classically
found in the central and peripheral neurons where NO plays a role in
neurotransmission and neuromodulation. eNOS is largely found in endothelial
cells and has a substantial role in blood pressure regulation
(Dominiczak and Bohr, 1995).
These two NOS isoforms are regulated by Ca2+ and
calmodulin and are constitutively expressed in tissues. In contrast, iNOS is
widely distributed among immune cells, including macrophages and glial cells,
is induced by various stimuli (e.g., endotoxin), and is activated independent
of Ca2+ (Jacobs et
al., 1997). The recent development of compounds that possess
relative selectivity for inhibiting different isoforms of NOS allows
identification of the specific NOS isoforms involved in specific
physiological, pathological, or pharmacological functions.
The aim of the present study was to use isoform-selective NOS inhibitors and determine whether their influences on N2O antinociception were consistent with an involvement of the neuronal form of NOS.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Antinociceptive Testing in Mice. Antinociception was assessed using the abdominal constriction test. The mice were treated i.p. with 0.1 ml/10 g b.wt. of 0.6% glacial acetic acid in distilled water and immediately placed into the test chamber; exactly 5 min later, the number of abdominal constrictions—length-wise stretches of the torso with concave arching of the back—was counted for each mouse over a 6-min observation period. In prior training sessions, the numbers of abdominal constrictions recorded in test animals were very consistent between trained observers who were or were not aware of drug treatment. Consequently, the observer for the experiments in this study was not blind to the drug condition of the various groups of mice.
Groups of one to six mice each were exposed to N2O inside an enclosed prefilled Plexiglas box (35 cm long x 20 cm wide x 15 cm high) with an airtight hinged lid. N2O in O2 was continuously delivered into the box using a standard dental sedation system (Porter, Hatfield, Pennsylvania). The amounts of N2O and O2 were varied within a total inflow rate of 10 l/min to achieve the desired test concentration (25% N2O: 2.5 l/min N2O and 7.5 l/min O2; 50% N2O: 5.0 l/min N2O and 5.0 l/min O2; and 70% N2O: 7.0 l/min N2O and 3.0 l/min O2). Gas entered the box through an inflow port at one end, circulated through the box, and exited through an outflow port at the other end. Exhausted gases were vented from the box to a nearby fume hood. The concentrations of N2O and O2 in the box were continuously monitored using a POET II anesthetic monitoring system (Criticare, Milwaukee, Wisconsin). Control animals were exposed to room air in lieu of N2O and O2.
In most experiments of this study, the protocol consisted of an i.p. injection of acetic acid followed by a 5-min exposure to N2O in the chamber then removal from the exposure chamber to a cage in room air, followed by a 6-min observation period, during which the number of abdominal constrictions was recorded. In room air-exposed mice, acetic acid-induced abdominal constrictions generally appear in 2 to 3 min, peak during the 6-min observation period, and slowly ebb with occasional constrictions occurring beyond 6 min.
To verify that the antinociceptive effect of N2O was still in effect during the 6-min observation time, three additional groups of mice were tested under modified conditions. As represented in the left panel of Fig. 1, the atmosphere during the 6-min observation period was varied from all N2O to all room air with two intermediate states wherein mice were transferred from N2O to room air 2 and 4 min into the 6-min observation period.
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The antinociceptive effect of N2O in different treatment groups of mice was quantified using the following formula: % antinociception = 100 x (no. constrictions in control mice – no. in control mice in exposed mice)/(no. constrictions in control mice). Separate vehicle-treated groups of mice were used as controls.
Assay of Neuronal Nitric-Oxide Synthase Activity. Mice were pretreated s.c. or i.c.v. with different doses of each NOS inhibitor. After pretreatment times of 30 min for S-methyl-L-thiocitrulline (SMTC) and N5-(1-iminoethyl)-L-ornithine (L-NIO) and 60 min for 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), the mice were euthanized by decapitation for collection of cerebella following s.c. pretreatment or whole brains following i.c.v. pretreatment. NOS activity was determined in the cerebellar or brain homogenate by the conversion of [14C]L-arginine to [14C]L-citrulline. The cerebellum or whole brain was homogenized in 2 volumes of Tris-HCl buffer (50 mM, pH 7.4), containing 2 mM EDTA and 2 mM EGTA, and centrifuged at 12,000 rpm at 4°C for 5 min. Twenty microliters of supernatant were added to test tubes containing 50 mM Tris-HCl buffer, 10 mM NADPH, 6 mM CaCl2, 6 mM tetrahydrobiopterin, 2 mM flavin adenine dinucleotide, 2 mM flavin mononucleotide, and 0.5 µCi [14C]L-arginine monohydrochloride (Amersham Biosciences, Piscataway, NJ) in a final volume of 40 µl at pH 7.4. Following incubation at 37°C for 30 min, the reaction was terminated by the addition of 50 mM HEPES buffer containing 5 mM EDTA and resin. Then the reaction mixture was applied onto 1.5-ml columns of Dowex AG50WX-8 (Bio-Rad, Hercules, CA). [14C]L-citrulline was quantified by scintillation spectroscopy of 10-ml aliquots of the flow through. The protein concentration was determined using a standard protein assay kit (Pierce Chemical Company, Rockford, Illinois). NOS activity was expressed in terms of picomoles of citrulline formed per milligram of protein per minute and then expressed as a percentage of control.
Measurement of Systolic Blood Pressures. Systolic blood pressure measurements were made noninvasively by the plethysmographic (tail-cuff) technique, using a model 59 pulse amplifier and dual channel recorder (IITC, Inc., Life Science, Woodland Hills, CA). Mice were anesthetized with an i.p. injection of ketamine (150 mg/kg) and xylazine (12.5 mg/kg). The mouse tail was inserted through the inflatable cuff of the sensor block, which also contained the photoelectric sensor and light source. The cuff was inflated to occlude the tail blood supply. As the pressure was slowly released, a sensitive pulse transducer detected the return of blood flow, and the "breakthrough" SBP was determined from the strip chart. The tail-cuff measures were derived from the average of three measurements per animal. In NOS inhibitor-treated mice, mice received either s.c. or i.c.v. injections of SMTC or L-NIO after a resting SBP was established (which generally required 15 min). After a 30-min pretreatment time, SBPs were determined and compared with the resting SBP.
Drugs. The following drugs were used in this research: N2O, U.S.P., and O2, U.S.P. (A and L Welding, Spokane, Washington), SMTC (Sigma-Aldrich, St. Louis, Missouri), AMT (Sigma-Aldrich), and L-NIO (Alexis, San Diego, California).
For s.c. or i.p. pretreatments, drugs were administered in an aqueous solution in injection volumes of 0.1 ml/10 g b.wt. For i.c.v. injections, the mice were briefly anesthetized with halothane, U.S.P. (Halocarbon, River Edge, New Jersey), and a volume of 5 µl of drug solution or vehicle was injected into the lateral cerebral ventricle using a hand-held 10-µl microsyringe (Hamilton, Reno, Nevada) at a point on the calvarium 1.0 mm lateral to and 2.0 mm caudal to bregma and to a depth of 2.5 mm from the skull surface.
Statistical Analysis of Data. In the abdominal constriction test,
the AD50 values and 95% confidence intervals were determined and
compared by the method of Litchfield and Wilcoxon
(1949). In the chemical
experiments, the significance of difference between treatment groups was
determined by one-way analysis of variance and a post hoc Tukey test.
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Results |
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Influence of Isoform-Selective NOS Inhibitors on N2O Antinociception in Mice. The s.c. pretreatment with 10, 30, or 50 mg/kg SMTC, the nNOS inhibitor, antagonized N2O antinociception in a dose-related manner, as indicated by a progressive rightward shift of the N2O antinociception dose-response curve (Fig. 2). The i.c.v. pretreatment with 1.0 µg SMTC/mouse also significantly attenuated N2O antinociception (Fig. 3). The s.c. pretreatment with 10 or 30 mg/kg L-NIO, the eNOS inhibitor, resulted in antagonism of N2O antinociception only at the higher dose (Fig. 4). The s.c. pretreatment with 1.0 mg/kg AMT, the iNOS inhibitor, failed to influence N2O antinociception (Fig. 5). None of these NOS inhibitors administered alone suppressed abdominal constrictions.
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Table 1 compares the AD50 values for N2O antinociception in the various treatment groups depicted in Figs. 2, 3, 4, 5. There is a significant increase in the AD50 values for N2O antinociception in treatment groups receiving any of two s.c. doses of SMTC, the i.c.v. dose of SMTC, or the higher dose of L-NIO. Conversely, there is no appreciable change in the AD50 values for N2O antinociception in treatment groups receiving AMT or the lower dose of L-NIO.
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Influence of NOS Inhibitors on Cerebellar NOS Activity in Mice. The s.c. pretreatment with increasing doses of SMTC and L-NIO resulted in a significant and dose-dependent reduction of cerebellar NOS activity (Fig. 6). On the other hand, there was no significant effect of AMT on cerebellar NOS activity. The i.c.v. pretreatment with 1.0 µg of SMTC/mouse also significantly reduced whole-brain NOS activity.
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Influence of NOS Inhibitors on Mean SBP. The s.c. treatment with increasing doses of SMTC also significantly elevated the mean SBP, albeit not in dose-related fashion (Table 2). When SMTC was administered in an i.c.v. dose of 1.0 µg/mouse, there was no change in mean SBP when compared with the vehicle treatment group. On the other hand, s.c. treatment with L-NIO caused a dose-dependent increase in the mean SBP.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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), neuroendocrine regulation
(Rivier, 2001), synaptic
plasticity (Hölscher,
1997), behavior (McLeod et
al., 2001), thermoregulation (Kamerman et al., 2000), food intake
(Kamerman et al., 2002), pain
(Luo and Cizkova, 2002), and neurotoxicity
(Mohanakumar et al.,
2002).
NOS catalyzes the five-electron oxidation of L-arginine to
L-citrulline and the free radical NO. Three major isoforms of NOS
have been described: nNOS, which is found predominantly in the brain, eNOS,
which is found in vascular endothelium, and iNOS, which is present in
activated macrophages. Inhibitors of NOS are invaluable tools in investigating
physiological or pharmacological roles of NO, and extensive research has
identified inhibitors with relative selectivity for each NOS isoform. SMTC is
considered a potent nNOS inhibitor with a 10-fold selectivity for nNOS
compared with eNOS and 28-fold for nNOS compared with iNOS
(Furfine et al., 1994).
L-NIO is approximately 8-fold more potent against eNOS than nNOS
and 4-fold more potent against eNOS than iNOS
(Rees et al., 1990;
McCall et al., 1991). On the
other hand, AMT is a selective inhibitor of iNOS, being 10-fold more potent
against iNOS than nNOS and 42-fold more potent against iNOS than eNOS
(Nakane et al., 1995;
Tracey et al., 1995).
Consistent with many earlier reports from our laboratory (Quock et al.,
1990,
1993;
Quock and Mueller, 1991;
McDonald et al., 1994),
exposure to N2O evoked a concentration-related antinociception in
mice. The current findings also demonstrate that a 5-min exposure to
N2O suppresses abdominal constrictions for at least 6 min following
termination of N2O exposure and removal to room air. Hence, it
would appear that continuous inhalation of N2O is not necessary for
continued antinociception. N2O must, therefore, activate a
mechanism or cascade that continues to its ultimate conclusion
(antinociception) despite termination of exposure and the rapid elimination of
N2O from the body in the expired air. That central mechanism is
hypothesized to be the stimulated neuronal release of dynorphin with
subsequent activation of central -opioid receptors
(Branda et al., 2000;
Cahill et al., 2000).
The N2O-induced antinociceptive effect was dose dependently
antagonized by SMTC and L-NIO but not AMT. The antagonism was in
agreement with earlier findings of an inhibitory effect of the nonselective
NOS inhibitors L-NAME and L-NOARG on N2O
antinociception (McDonald et al.,
1994). Superficially, these findings implicate the neuronal and
endothelial isoforms of NOS in N2O antinociception. Since most NO
in the brain likely results from an action of nNOS, the question is whether
the eNOS of the cerebral vasculature might be involved in N2O
antinociception.
First, we measured NOS activity in the cerebellum as a general index of
nNOS activity after treatment of each NOS inhibitor. As expected, SMTC, a
selective nNOS inhibitor, reduced the cerebellar NOS activity in a
dose-dependent manner. AMT is reportedly a selective inhibitor of iNOS
(Nakane et al., 1995). Despite
a recent study questioning its selectivity
(Boer et al., 2000), it also
had no effect on cerebellar NOS activity at a dose that significantly reduced
the lipopolysaccharide-induced increase in plasma nitrites and nitrates
(Tracey et al., 1995).
Ostensibly selective for eNOS, L-NIO also reduced cerebellar NOS
activity in a dose-related manner. Low-dose L-NIO (10 mg/kg) had no
effect on N2O antinociception and no effect on cerebellar NOS
activity. Nevertheless, high-dose L-NIO (30 mg/kg) antagonized
N2O antinociception and inhibited cerebellar NOS activity. This is
likely the result of loss of selectivity for eNOS and emerging inhibition of
nNOS at higher doses (30 mg/kg).
Secondly, we attempted to identify an appropriate index of eNOS activity.
Attempts to measure NOS activity in descending aorta were fraught with
difficulty because of limited tissue mass and low levels of NOS activity.
Since eNOS is largely found in endothelial cells and is thought to have a
substantial role in blood pressure regulation
(Dominiczak and Bohr, 1995), it
was thought that SBP might be sensitive to changes in eNOS activity. It is
known that inhibition of eNOS can induce an increase in SBP
(Rees et al., 1990). In the
present study, both SMTC and L-NIO elevated mean SBP. Although SMTC
was previously characterized as a selective inhibitor of the nNOS isoform
(Furfine et al., 1994), all
three doses of SMTC significantly increased the mean SBP, which was consistent
with earlier reports that SMTC elevates SBP
(Narayanan et al., 1995). This
effect has been explained on the basis of possible inhibition of nNOS in
cardiovascular-regulating regions of the brain
(Ollerstam et al., 1997), but
detailed mechanisms remain unclear. These SBP-increasing effects of SMTC were
not dose-related and were not correlated to antagonism of N2O
antinociception in a dose-dependent manner as did inhibition of cerebellar NOS
activity.
In the present study, L-NIO caused significant dose-related
increases in the mean SBP. This SBP-elevating effect of L-NIO was
weaker than that of SMTC, however. Although previous reports showed that
L-NIO increased SBP significantly, that effect was 10 times weaker
than the other arginine analog inhibitors (L-NAME or
L-NOARG) (Rees et al.,
1990). In our preliminary experiments, the SMTC effect was
comparable to that of L-NOARG. Therefore, the present results are
consistent with the results of earlier studies.
In addition to experiments using systemic pretreatment with NOS inhibitors,
SMTC was also introduced directly into the brain. SMTC, administered via the
i.c.v. route, produced a significant antagonism of N2O
antinociception. This pretreatment also significantly cerebellar NOS activity
without causing an elevation in mean SBP. In earlier research,
L-NAME, a nonselective NOS inhibitor, was also found to be an
effective antagonist of N2O antinociception following i.c.v.
pretreatment (McDonald et al.,
1994).
In conclusion, N2O antinociception in the mouse abdominal constriction test was most effectively antagonized by the selective nNOS inhibitor SMTC in a dose-dependent manner. This antagonism of antinociception was dose dependently correlated with inhibition of cerebellar NOS activity but not with increasing SBP. At low doses, the selective eNOS inhibitor L-NIO was ineffective in antagonizing N2O antinociception or inhibiting cerebellar NOS activity. A higher dose of L-NIO not only reduced N2O antinociception but also inhibited cerebellar NOS activity. L-NIO also caused a dose-related increase in SBP. It is presumed that, at high doses, L-NIO loses its selectivity for eNOS and also affects nNOS. The selective iNOS inhibitor AMT was ineffectual in antagonizing N2O antinociception and also failed to reduce cerebellar NOS activity. These results suggest that the neuronal isoform of NOS is involved in mediation of the antinociceptive effect of N2O in the mouse.
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Footnotes |
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ABBREVIATIONS: NO, nitric oxide; NOS, nitric-oxide synthase; nNOS,
neuronal nitric oxide synthase; eNOS, endothelial nitric oxide synthase; iNOS,
inducible nitric oxide synthase; SMTC,
S-methyl-L-thiocitrulline; L-NIO,
L-N5-(1-iminoethyl)ornithine; AMT,
2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; SBP, systolic blood
pressure; L-NAME, L-N
-nitro
arginine methyl ester; L-NOARG,
L-N-nitro arginine; U.S.P., United
States Pharmacopeia.
Address correspondence to: Dr. Raymond M. Quock, Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, P.O. Box 646534, Pullman, WA 99164-6534. E-mail: quockr{at}wsu.edu
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,
vehicle (control); 
, 10 mg/kg; 
, 30 mg/kg; 
, 50 mg/kg.
Symbols represent the mean percentage of antinociceptive response in 9 to 22
mice per treatment group.
, 1.0 mg/kg.
Symbols represent the mean percentage of antinociceptive response in 10 to 18
mice per treatment group.