Figure 4. Co-treatment with low doses of systemic metformin and local resveratrol inhibit acute mechanical hypersensitivity and hyperalgesic priming induced by plantar incision.

All animals received a plantar incision on the left hind paw. Metformin (100 or 150 mg/kg) was injected systemically for 4 consecutive days, starting 2 days prior to surgery, the day of surgery, and 1-day post surgery (red arrows) and resveratrol (1 or 3 μg) was injected in the left hind paw on the day of the surgery and 1-day post-surgery (purple arrows) and animals assessed for mechanical sensitivity by von Frey hair stimulation at the indicated time points. A) Co-treatment with systemic metformin (100 mg/kg) and local resveratrol (1 μg) significantly improved recovery from plantar incision-induced acute hypersensitivity. B) Cumulative treatment effect size of individual doses versus vehicle or combined doses versus vehicle is shown as area over the vehicle curve. C) Co-treatment with systemic metformin (150 mg/kg) and local resveratrol (3μg) significantly inhibited plantar incision-induced acute hypersensitivity. D) Co-treatment with systemic metformin (100 mg/kg) and local resveratrol (1 μg) significantly interfered with development of plantar incision-induced hyperalgesic priming precipitated by PGE₂ injection on day 14 after incision. D) Cumulative treatment effect size of individual doses versus vehicle or combined doses versus vehicle is shown as area over the vehicle curve. F) Co-treatment with systemic metformin (150 mg/kg) and local resveratrol (3 μg) significantly inhibited plantar incision-induced hyperalgesic priming precipitated by PGE₂ injection on day 14 after incision. G) Summary diagram of mechanisms underlying metformin and resveratrol activation of AMPK. Behavioral data was analyzed by two-way ANOVA with Bonferroni post hoc test. * p < 0.05, ** p < 0.01, *** p < 0.001 (n = 6 per group).