PMC

Carotid distension was used as an indirect measure of blood pressure in awake, behaving animals. A. Carotid distension was challenged by intrathecal morphine, clonidine or both. While clonidine (▪) reduced carotid distension in a dose-dependent manner, morphine (•) was ineffective. When the agonists were co-administered at a constant ratio of 1∶1 (○ morphine; □ clonidine), the potency and efficacy of the combination was not different from that of clonidine given alone. B. Systemically administered clonidine (▪), but not morphine (•), reduced carotid distension in a dose-dependent manner. Neither the potency nor the efficacy of the combination of morphine∶clonidine at a dose ratio of 10∶1 (○ morphine; □ clonidine) were different from clonidine given alone. Data pictured were obtained 10 minutes following intrathecal (Figure 4A) and 15 minutes following systemic administration (Figure 4B). Error bars represent ±SEM for each dose point (n = 6-10 animals/dose). See for ED₅₀ values. Note: 100% MPE was artificially set at 300 µm for carotid distension (baseline ∼700 µm) to facilitate dose-response and isobolographic analysis.

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 for ED₅₀ values.

A. Rotarod retention was challenged by intrathecal morphine, clonidine or both. Morphine (•) and clonidine (▪) inhibited rotarod performance in a dose-dependent manner with similar potency. When the agonists were co-administered at a constant ratio of 1∶1 (○ morphine; □ clonidine), no increases in potency or efficacy were observed. A′. Isobolographic analysis applied to the data from Figure 2A. 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 (•) is not significantly (p<0.05; t-test) different from the theoretical additive ED₅₀ (○), indicating that the interaction is additive. B. Systemically administered morphine (•) and clonidine (▪) dose-dependently inhibited rotarod performance when administered 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 2B. The observed combination ED₅₀ (•) is not significantly (p<0.05; t-test) different than the theoretical additive ED₅₀ (○), indicating that the interaction is additive. Data pictured were obtained 15 minutes following intrathecal (Figures 2A, A′) and 20 minutes following systemic administration (Figures 2B, B′). Error bars represent ±SEM for each dose point (n = 6–10 animals/dose). See for ED₅₀ values.

A. Heart rate was challenged by intrathecal morphine, clonidine or both. Morphine (•) and clonidine (▪) inhibited heart rate in a dose-dependent manner. When the agonists were co-administered at a constant ratio of 1∶1 (○ morphine; □ clonidine), no increases in potency or efficacy were observed. A′. Isobolographic analysis applied to the data from Figure 3A. 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 respective 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 (•) is not significantly (p<0.05; t-test) different from the theoretical additive ED₅₀ (○), indicating that the interaction is additive. B. Systemically administered morphine (•) and clonidine (▪) dose-dependently inhibited heart rate when administered 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 3B. The observed combination ED₅₀ (•) is significantly (p<0.05; t-test) higher than the theoretical additive ED₅₀ (○), indicating that the interaction is sub-additive. Data pictured were obtained 10 minutes following intrathecal (Figures 3A, A′) and 15 minutes following systemic administration (Figures 3B, B′). Error bars represent ±SEM for each dose point (n = 6–10 animals/dose). See for ED₅₀ values. Note: 100% MPE was artificially set at 300 beats per minute (baseline ∼800) to facilitate dose-response and isobolographic analysis.