(A) Dose-response curve: Groups of C57BL/6J mice were supraspinally (icv) administered MP1207, MP1208, morphine and U50,488h and antinociception measured using the 55°C tail withdrawal assay at peak effect. Data are shown as mean % antinociception (MPE) ± SEM. ED50 (with 95% CI) values = 6.1 (4.1–8.9) nmol, 7.2 (5.0–10.2) nmol, 4.77 (1.49–28.8) nmol, and 8.8 (5.7–13.5) nmol were calculated for MP1207, MP1208, morphine and U50,488h respectively. (B–C) Antinociceptive time course: Effect of MP1207 (B) and MP1208 (C) at doses of 1, 3, 10, 30, and 100 (n = 8 each group, with n = 16 for MP1208 at 30 nmol) with repeated measures over time. (D–E) MP1207/08 analgesia in KO mice: Analgesic effect of MP1207 (30 nmol icv, D ) and MP1208 (35 nmol icv, E) was evaluated in groups (n = 8) of WT (C57BL/6J), MOR KO, KOR KO, and DOR KO mice. Antinociception of MP1207/08 remained intact in DOR KO mice while it was attenuated in MOR KO and KOR KO mice. Results for MP1207 were analyzed with one-way ANOVA followed by Dunnett’s post hoc test; F3,28=10.11, p=0.0001.**p=0.005 relative to WT, ****p<0.0001 relative to WT, ns = p>0.05 relative to WT. Similarly, MP1208 results were analyzed with one-way ANOVA followed by Dunnett’s post hoc test, F3,28=15.35, p<0.0001.**p=0.005 relative to WT, ****p<0.0001 relative to WT, ns = p>0.05 relative to WT. All values are expressed as the mean MPE ± SEM. (F) Conditioned place preference or aversion (CPP/CPA): Place conditioning evaluation of MP1207, 1208, morphine, U50,488h, saline and vehicle in C57BL/6J mice after icv administration. Following determination of initial preconditioning preferences (pre-CPP), mice were place‐conditioned daily for 2 days with MP1207 (30 nmol, n = 23 and 100 nmol, n = 24), MP1208 (100 nmol, n = 26), U50,488 (100 nmol, n = 19) or morphine (30 nmol, n = 12) and examined the fourth day for final conditioned place preference (post-CPP). Mean differences in time spent on the drug‐paired side ± SEM are presented. *p=0.03 (morphine) or **p=0.003 (U50,488h), significantly different from matching pre-conditioning preference; unpaired t-test with Welsch’s correction. Both MP1207/08 were neither reinforcing nor aversive in mice.