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NMDA As It Relates To Tolerance
NMDA As It Relates To Tolerance
Introduction
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Methods
Subjects
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542
Fig. 1
20
WT
15
Drugs
Drug effects were expressed as a percentage of the maximal possible effect (% MPE) using the following formula:
% MPE
Results
Figure 1 shows a temperatureeffect curve for NR1 KD
mice and the WT controls. Analysis of variance confirmed
an effect of temperature, but no effect of genotype.
Pairwise comparisons of the temperature effects indicated that response latencies at the lower temperatures
(i.e. 46, 48 and 508C) were significantly different
(P < 0.05) from the response latencies at the higher
temperatures (i.e. 52, 53 and 568C). No differences were
observed in baseline response latency between NR1 KD
Latency (s)
Withdrawal jumping
KD
10
5
0
46
48
50
52
54
56
Temperature (C)
Temperature-dependent effects on the hot plate in NR1 knockdown
(NR1 KD) and wild-type (WT) mice. Horizontal axis: hotplate
temperature (degrees Celsius). Vertical axis: latency to respond on the
hot plate in seconds. Temperature-effect determinations were
conducted at 15-min intervals. (n = 7 or 8).
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Fig. 2
WT
KD
100
% MPE
75
50
25
0
25
0.32
1.0
3.2
10.0
Morphine (mg/kg)
32.0
0.32
1.0
3.2
I-Methadone (mg/kg)
10.0 0.01
0.03
0.1
Fentanyl (mg/kg)
0.3
Doseeffect curves for morphine (0.3232 mg/kg), l-methadone (0.3210 mg/kg) or fentanyl (0.010.3 mg/kg) in NR1 knockdown (KD) and wildtype (WT) mice. Horizontal axis: dose of morphine, l-methadone or fentanyl (milligrams per kilogram). Vertical axis: antinociception quantified as
percentage of the maximal possible effect (%MPE). Doseeffect determinations were conducted cumulatively at 30-min (morphine and l-methadone)
or 15-min (fentanyl) intervals. (n = 6 or 7).
Effective dose 50 values (mg/kg) ( 95% confidence limits) and dose ratios for morphine and l-methadone alone and in
combination with 1.0 mg/kg naltrexone
Table 1
Drug
Genotype
Morphine
WT
NR1 KD
WT
NR1 KD
l-Methadone
(1.763.67)
(8.4712.73)
(0.721.44)
(3.035.09)
+ NTX (CL)
9.67
32.54
5.79
12.14
(8.0411.60)
(26.5939.81)
(4.297.83)
(9.0916.20)
(2.695.53)
(2.384.10)
(3.608.85)
(2.164.23)
CL, confidence limits; KD, knockdown; NTX, naltrexone; WT, wild type.
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Fig. 3
Fig. 4
100
100
Prechronic
Postchronic
50
% MPE
75
WT
25
0
25
0.32
1.0
3.2
10.0 32.0
Morphine (mg/kg)
100.0
25
WT
KD
Prechronic
Postchronic
50
KD
100
25
0
25
0.32
1.0
3.2
10.0 32.0
Morphine (mg/kg)
100.0
% MPE
50
100
75
75
75
50
25
0
WT
KD
Genotype
Discussion
This study used mice with significantly reduced NR1
subunit expression to examine the role of the NMDA
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Fig. 5
100
Genotype Morphine plus Prechronic (CL) Postchronic (CL) Dose ratio (CL)
WT
% MPE
75
WT
50
NR1 KD
25
0
Saline
(n = 11)
LY235959
(n = 11)
Saline
(n = 8)
LY235959
(n = 9)
4.59
(3.795.56)
1.91
(1.482.48)
10.30
(8.2812.80)
9.85
(7.6612.67)
12.25
(9.2016.31)
13.14
(10.4316.55)
24.21
(11.7250.04)
31.97
(18.8854.11)
2.80
(2.023.85)
7.03
(5.0510.28)
2.59
(1.564.19)
3.24
(1.975.35)
25
C
0.32
1.0
3.2
10.0
32.0
Morphine (mg/kg)
100
KD
% MPE
75
50
25
0
25
C
0.32
1.0
3.2
10.0
32.0
Morphine (mg/kg)
Saline
0.32 LY235959
0.1 LY235959
1.0 LY235959
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Conflicts of interest
Acknowledgements
Support was provided by grants from the National Institutes
of Health, RO1-DA002749 and T32-DA007244.
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