Results following 7 days of morphine treatment Table 1 and Fig.
B . Kest et al. Brain Research 879 2000 17 –22
19
and all mice received a single 10 mg kg morphine 4.160.63; females: 3.960.37, Day 4 males 3.860.41;
injection. Withdrawal latencies were re-assessed at 30-min females: 4.060.29 or Day 8 males: 4.160.37; females:
intervals for 2 h. Mice were then subject to 3 days of 4.260.40. In addition, male and female morphine ED
50
morphine injections according to the dosing schedule values obtained on Day 1, prior to the start of the 3- or
above. On Day 4, baseline latencies and morphine analge- 7-day tolerance induction protocol, were practically identi-
sia were again determined at 30-min intervals for 2 h. cal and were thus pooled. As illustrated in Fig. 1, 3 days of
Withdrawal latencies at peak analgesia 30 min for each morphine administration produced a rightward shift in the
sex on Day 1 and 4 were converted to MPE scores morphine dose–response curve in both sexes on Day 4
[post-drug latency–baseline
latency cutoff latency–
relative to Day 1. Table 1 shows that the resultant baseline latency3100], and compared. The area under the
morphine ED estimates was significantly increased on
50
time3latency curve AUC; min3s for males and females Day 4 males: 12.2 mg kg; females: 28.6 mg kg relative
was used to calculate total analgesia AUC maximum to Day 1 males: 4.1 mg kg; females: 6.2 mg kg in both
possible AUC and compared. males and females, indicative of tolerance. However, the
magnitude of tolerance was different between sexes. 2.6. Data analysis
Whereas morphine potency was similar in males and females on Day 1, equivalent dose–response shifts and
Morphine dose–response data were analyzed using the ED
estimate increases were not obtained on Day 4 Fig.
50
BLISS
-21 computer program. This program maximizes the 1 and Table 1, respectively. In females, there was an
log-likelihood function to fit a parallel set of Gaussian approximately 4.6-fold rightward shift in the morphine
sigmoid curves to the dose–response data, and provides dose–response curve relative to an only three-fold shift in
ED values, 95 confidence intervals CI, and estimates
males Fig. 1, resulting in changes in morphine potencies
50
of relative potency [42]. Baseline tail-withdrawal latencies, on Day 4 relative to Day 1 of 0.34 in males but 0.22 in
and peak and total morphine analgesia between sexes on females Table 1. ED
estimates from morphine naive
50
Day 1 was compared using an independent t-test. A two- mice Day 1 in morphine-treated mice and Day 4 in saline
way one within, one between repeated measures ANOVA control mice did not differ within or between sex,
was used to compare peak and total morphine analgesia confirming that there were no significant initial differences
on Days 1 and 4. An a level of 0.05 was used for all
in morphine sensitivity between sexes, and indicating no comparisons.
effect of the repeated injection protocol. Although morphine tolerance is increased in both sexes
when morphine treatment and or cumulative are increased