Morphine and Clonidine Combination Therapy Improves Therapeutic Window in Mice: Synergy in Antinociceptive but Not in Sedative or Cardiovascular Effects
Figure 1
Effects of Morphine and Clonidine in the Tail Flick Antinociception Assay.
A: Intrathecally delivered morphine (•) and clonidine (▪) dose-dependently inhibited thermal nociception with similar potency and efficacy. When co-administered at a constant dose ratio of 1∶1 (○ morphine; □ clonidine), both potency and efficacy were increased. A′: Isobolographic analysis applied to the data from Figure 1A. The y-intercept represents the ED50 for morphine and the x-intercept represents the ED50 for clonidine. The lines directed from each ED50 value toward zero represent the lower 95% confidence limits of each ED50. The line connecting these two points is the theoretical additive line. The unfilled circle on the theoretical additive line represents the calculated theoretical ED50 value of the combination if the interaction is additive. The observed combination ED50 (•) was significantly (p<0.05; t-test) lower than the theoretical additive ED50 (○), indicating that the interaction is synergistic. B. Systemically administered morphine (•) and clonidine (▪) dose-dependently inhibited thermal nociception when administered either alone or in combination at a constant morphine∶clonidine dose ratio of 10∶1 (○ morphine; □ clonidine). B′: Isobolographic analysis applied to the data from Figure 1B. The y-intercept represents the ED50 for morphine and the x-intercept represents the ED50 for clonidine. The observed combination ED50 (•) was significantly (p<0.05; t-test) lower than the theoretical additive ED50 (○), indicating that the interaction is synergistic. Data pictured were obtained 10 minutes following intrathecal (Figures 1A, A′) and 15 minutes following systemic administration (Figures 1B, B′). Error bars represent ±SEM for each dose point (n = 6–10 animals/dose). See Table 1 for ED50 values.