Article Figures & Data
Figures
- Fig. 1.
Brain uptake of radioactive morphine, An2-morphine, and An2-M6G measured by in situ brain perfusion. (A) Time course of brain uptake of [3H]-morphine, [125I]-An2-morphine and [125I]-An2-M6G. Representation of the Vd in brain homogenate. (B) Quantification of [3H]-morphine, [125I]-An2-morphine, and [125I]-An2-M6G in total brain, capillaries, and parenchymal fractions after 2 minutes of perfusion. Data represent mean ± S.E.M. (n = 3 to 4). **P < 0.01; ***P < 0.001; two-way ANOVA test followed by Tukey’s multiple comparison test.
- Scheme 1.
(A) Synthesis of (morphine-PEG)3-angiopep-2 (compound 3). (B) Synthesis of (M6G)3-angiopep-2 (compound 7).
- Fig. 2.
Antinociceptive effects of intravenous morphine and An2-morphine in the tail-flick assay. The antinociceptive effects of morphine and An2-morphine were evaluated by measuring the time to tail withdrawal in the tail-flick assay. Rats were treated intravenously with saline or with increasing doses of either morphine sulfate (MS) [0.3 mg/kg (n = 10), 1 mg/kg (n = 7), and 3 mg/kg (n = 10)] (A) or An2-morphine [0.3 mg/kg (n = 10), 1 mg/kg (n = 10), and 3 mg/kg (n = 9)] (D). For each dose, the %MPE was calculated for morphine and An2-morphine, as shown in (B and E), respectively. The AUC representing the total drug exposure across time (i.e., 120 minutes) after administration of increasing doses of MS is represented in (C), whereas the AUC of equimolar doses of An2-morphine is shown in (F). *P < 0.05; **P < 0.01; ****P < 0.0001 compared with the saline group; one-way ANOVA followed by Dunnett’s multiple comparisons test.
- Fig. 3.
Antinociceptive effects of intravenous M6G and An2-M6G in the tail-flick assay. The antinociceptive effects of M6G and An2-M6G were evaluated by measuring the time to tail withdrawal in the tail-flick assay. Rats were treated intravenously with saline or with increasing doses of either M6G [1.5 mg/kg (n = 10), 3 mg/kg (n = 7), and 4.5 mg/kg] (n = 10) (A) or An2-M6G [1.2 mg/kg (n = 6), 4 mg/kg (n = 9), 8 mg/kg (n = 5), and 12 mg/kg] (n = 6) (D). For each dose, the %MPE was calculated for M6G and An2-M6G (B and E). The AUC calculated for the whole period of time is represented in (C and F). *P < 0.05; **P < 0.01; ****P < 0.0001 compared with the saline group; one-way ANOVA followed by Dunnett’s multiple comparisons test.
- Fig. 4.
Antinociceptive effects of intravenous morphine, An2-morphine, morphine-6-glucuronide, and An2-M6G in the hot-plate test. The antinociceptive effects of morphine sulfate (MS), An2-morphine, M6G, and An2-M6G were evaluated by measuring the paw-licking behaviors of adult male CD1 mice in the thermal hot-plate assay. Mice were injected intravenously with saline, 10 mg/kg of MS or 30 mg/kg of An2-morphine (A) or saline, 1.5 mg/kg of morphine, 3 mg/kg of M6G, and 6 mg/kg of An2-M6G (n = 5 per group) (D). For each drug, the %MPE was calculated, as shown in (B and E). The AUC after administration of equimolar doses of MS and An2-morphine is represented in (C), whereas the AUC of equimolar doses of MS, M6G, and An2-M6G are shown in (F). **P < 0.01; ***P < 0.001; ****P < 0.0001 compared with saline group; #P < 0.05; ####P < 0.0001 compared with An2-M6G; one-way ANOVA test followed by Tukey’s multiple comparison test.
- Fig. 5.
Antinociceptive effects of subcutaneous morphine, An2-morphine, morphine-6-glucuronide, and An2-M6G in the tail-flick assay. The antinociceptive effects of morphine sulfate (MS), An2-morphine, M6G, and An2-M6G were evaluated by measuring the time to tail withdrawal in the tail-flick assay. Rats were injected subcutaneously with saline, 5 mg/kg of MS, or 20 mg/kg of An2-morphine (A) or saline, 3 mg/kg of morphine, 5 mg/kg of M6G, and 12 mg/kg of An2-M6G (n = 9 to 10 per condition) (D). For each drug, the %MPE was calculated, as shown in (B and E). The AUC after administration of equimolar doses of MS and An2-morphine is represented in (C), whereas the AUC of equimolar doses of MS, M6G, and An2-M6G is shown in (F). ***P < 0.001; ****P < 0.0001 compared with saline group; #P < 0.05; ####P < 0.0001 compared with MS group; $$P < 0.01; $$$P < 0.001; one-way ANOVA test followed by Tukey’s multiple comparison test. &, the baseline was used at 180 minutes to calculate the AUC of morphine group until 180 minutes.
Tables
- TABLE 2
Effect of morphine, An2-M6G, and An2-morphine on the gastrointestinal tract motility
Saline, MS (1, 5 and 10 mg/kg), An2-M6G (4 and 20 mg/kg), and An2-morphine (20 mg/kg) were injected subcutaneously 30 min before force-feeding with a charcoal meal solution. The progression of the charcoal meal in the intestine was measured 1 h after force-feeding.
Treatment Saline Morphine Sulfate (MS) An2-M6G An2-morphine n 10 10 10 10 10 10 10 Dose (mg/kg) 1 5 10 4 20 20 Equimolar MS 1 5 5.5 Progression of the charcoal meal in the intestine (% ± S.E.M.) 73.4 ± 2.2 58 ± 2.7* 49.7 ± 2.7*** 28.6 ± 3.7**** 61.5 ± 3.3 59.7 ± 3.1$ 45.1 ± 5.1**** MS, morphine sulfate.
↵* P < 0.05, ***P < 0.001, and ****P < 0.0001 compared with saline group; $P < 0.05 An2-M6G (20 mg/kg) compared with An2-morphine (20 mg/kg); Kruskal-Wallis nonparametric test followed by Dunn’s multiple comparison test.
