Fig. 5. Co-administration of UK 14,304 (+ 5 pmol prazosin) and deltorphin II is synergistic in WT but not in D79N mice.A, SP-elicited behavior was challenged by intrathecal administration of either deltorphin II or UK 14,304 + 5 pmol prazosin (UK + P) or both in WT mice. UK + P (squares) and deltorphin II (circles) inhibited the behavior in a dose-dependent manner with similar potency and efficacy. When both UK 14,304 and deltorphin were co-administered, a constant potency ratio (1:1 molar agonist ratio) was maintained. The combination treatment (triangles) was ∼10-fold more potent than either drug given alone, an indication of a synergistic interaction. The abscissa for the combined treatment dose–response curves represent the dose of UK 14,304 in the presence of an equal potency ratio of deltorphin II. B, Isobolographic analysis was applied to the data from Figure 5A. They-intercept represents the ED50 (0.24 nmol; 95% CI = 0.09–0.63) for UK + P, and thex-intercept represents the ED50 (0.42 nmol; 95% CI = 0.21–0.87) for deltorphin II when each was administered alone for inhibition of SP-elicited behavior in WT mice. Theheavy line connecting the intercepts is the theoretical additive line. Coordinates for drug combinations falling below this line and outside the confidence limits indicate synergy. When the two compounds were co-administered in WT animals, the resultant ED50 (0.021 nmol; CI = 0.016–0.028) of UK + P in the presence of deltorphin II fell well below the additive line, indicating a synergistic interaction. Error bars parallel to each axis represent the lower 95% CI for each compound. The error bars on the combined dose point represent the upper and lower 95% CIs. C, SP-elicited behavior was challenged by intrathecal administration of either deltorphin II (circles) or UK + P (squares) or both (triangles) in D79N mice. The combination treatment (100:1 molar agonist ratio) failed to shift the UK + P dose–response curve in D79N animals, even though deltorphin II was otherwise effective at those doses. The abscissa values for the combined treatment dose–response curves represent the dose of UK 14,304 in the presence of an equal potency ratio of deltorphin II. D, Isobolographic analysis was applied to data from Figure 5C. The ED50 values for the drugs given alone were 51 nmol (95% CI = 22–118) for UK + P and 0.33 nmol (95% CI = 0.20–0.57) for deltorphin II. The ED50 for UK + P when co-administered with deltorphin II was 12 nmol (95% CI = 8.6–17). The 95% CI of the combined ED50 fell within the lower confidence 95% CIs of the theoretical additive line, indicating that the interaction between these two compounds in D79N mice was not significantly different from additive. This study has been repeated blind with similar results (data not shown).