MRS5698 potentiates morphine antinociception in morphine-tolerant rats. (a) Schematic of drug administration paradigm. (b) Effect of intrathecal MRS5698 on morphine (15 mg/kg; i.p) antinociception in rats with established morphine tolerance. On days 8–9 and 12–13, intrathecal MRS5698 (50 nmol) was administered with morphine. On days 10–11, intrathecal vehicle was administered with morphine. Effects of MRS5698 were blocked by intrathecal treatment with the A3AR antagonist MRS1523 (25 nmol). N = 6 for all groups. Two-way ANOVA, Sidak’s post hoc test (Interaction F(14,105) = 19.60, p < 0.0001; Time F(7,105) = 203.9, p < 0.0001; Treatment F(2,15) = 36.29, p < 0.0001). *Significance compared to Mor + Vehicle control (D8,9,12,13 p < 0.0001). #Significance compared to Mor + MRS5698/vehicle (D8,9,12,13 p < 0.0001). All data are presented as mean ± SEM