Fig. 2.
Body mass and behavioral tolerance in Tat transgenic mice were significantly impacted by Tat exposure and morphine treatment. a Time course of body mass in Tat(−) and Tat(+) mice exposed to repeated injections of saline or morphine for 8 days. Morphine significantly decreased body mass for Tat(−) and Tat(+) groups overall and across time. Further, Tat expression decreased body mass for Tat(+) mice compared to Tat(−) mice. All data are expressed as mean ± SEM. Statistical significance was assessed by ANOVAs followed by Tukey’s post hoc tests; *p = 0.003 main effect of drug; §p < 0.001 time × drug interaction; #p < 0.001 main effect of genotype. Morph short-term (8-day) morphine injections. n = 7–9 mice per group. b, c Assessment of morphine-induced antinociceptive tolerance in Tat(+) mice compared to Tat(−) mice after morphine or saline exposure for eight days. Each data point represents the mean of the percent maximum possible effect of tail withdrawal (tail flick) or paw withdrawal/lick (hot plate) relative to baseline as a function of acute morphine dose (mg/kg). b For the tail-flick assay repeated morphine exposure produced tolerance in Tat(−) and Tat(+) mice compared to their saline-exposed counterparts as indicated by the significant 3.2-fold and 6.7-fold increases in the potency ratios, respectively (ap < 0.05). Importantly, the 6.7-fold increase in potency for Tat(+) mice was significantly higher than the 3.2-fold increase for Tat(−) mice (based on non-overlapping 95% confidence interval, §p < 0.05, see Table 1 for details), indicating increased tolerance for Tat(+) compared to Tat(−) mice when repeatedly exposed to morphine. Note, as the potency ratio of 6.7 is based on an estimated ED50 value, caution should be exercised when interpreting the data. Nevertheless, the significant difference between Tat(−) and Tat(+) mice is supported by ANOVA results, specifically in response to an acute morphine injection of 64 mg/kg (†p = 0.009). c For the hot-plate assay morphine-induced tolerance was less robust. ANOVA results indicated significance at 8 mg/kg and/or 16 mg/kg as well as significant differences in ED50 values for Tat(+) mice exposed to saline versus morphine (based on non-overlapping 95% confidence interval, see Table 1 for details). However, the 2.7- and 4.4-fold increase in potency ratio for morphine exposure in Tat(−) and Tat(+) mice, respectively, was not significant. All data are expressed as mean ± SEM. Statistical significance was assessed by ANOVA followed by Tukey’s post hoc test; *p < 0.05 vs. 8 or 16 mg/kg acute morphine administration in the corresponding Tat mouse group exposed to repeated morphine; for Tat(+) mice: #p < 0.05 vs. Tat(+) mice exposed to repeated morphine. “PR” = potency ratio, as determined by the ED50 shift between the saline and morphine-exposed groups (see text for details), ap < 0.05; §p < 0.05 vs. 3.2-fold PR for Tat(−) mice. Morph short-term (8-day) morphine injections, MPE maximun possible effect, PR potency ratio. Tail flick, n = 7–9 mice per group; hot plate, n = 3–4 mice per group