Figure 12. LY2828360 reverses established tolerance to the anti-allodynic effects of morphine in male, and to a lesser extent in female CB2^f/f GFP mice, but not in advillin^Cre+/;CB2^f/f mice.

In all groups receiving morphine (10 mg/kg i.p.) alone on days 1-6 of administration, tolerance rapidly develops to morphine’s antinociceptive efficacy (A-H). In CB2^f/f GFP mice, following initiation of LY2828360 dosing (0.03 mg/kg or 0.1 mg/kg i.p.) in conjunction with morphine on days 7-12, the antinociceptive efficacy of morphine returned, alleviating ddC-evoked mechanical (A, C, E, G) and cold (B, D, F, H) hypersensitivity on days 9-12 of administration. LY2828360 produced a reversal of established morphine tolerance in male, and to a lesser extent in female CB2^f/f mice (A-H), but not in advillin^cre+/;CB2^f/f mice of either sex (C,D,G,H). ^###p<0.001 vs. baseline, ^:::p<0.001, ^::p<0.01, ^:p<0.05 CB2^f/f MOR+LY vs. all other groups, ^>p<0.05 CB2^f/f MOR+LY vs. CB2^f/f MOR+Veh, ^!p<0.05 CB2^f/f MOR+Veh vs. Adv cre+;CB2 f/f MOR+LY, ^<<p<0.01, ^<p<0.05 CB2^f/f MOR+Veh vs. all other groups, ^\p<0.05 CB2^f/f MOR+LY vs. vs. advillin^cre+/;CB2^f/f MOR+VEH, ⁻p<0.05 CB2^f/f vs. advillin^cre+/;CB2^f/f MOR+LY, “p<0.05 CB2^f/f vs. advillin^cre+/;CB2^f/f, ^~p<0.05 CB2^f/f MOR+LY vs. advillin^cre+/;CB2^f/f MOR+LY, ^/p<0.05 CB2^f/f MOR+Veh vs. advillin^cre+/;CB2^f/f MOR+LY. Two-way ANOVA, Tukey Multiple comparisons test post-hoc. (N=6-10 per group). Black bars indicate period of LY and morphine co-administration. For reversal condition, grey bar indicates period of vehicle+morphine administration (days 1-6), black bar indicates period of LY+morphine co-administration (days 7-12). MOR: morphine, LY: LY2828360, Adv: advillin, Veh: vehicle.