Systemic morphine-3-glucuronide administration fails to elicit tactile hyperalgesia in rats pretreated with the small molecule inhibitor of Toll-like receptor 4/myeloid differentiation protein-2 complex, Compound 15, or in Toll-like receptor 4 knockout mice. (A) Systemic morphine-3-glucuronide (M3G) (10 mg/kg, intraperitoneally) produced robust tactile hyperalgesia (n = 6, ANOVA, Bonferroni multiple comparison test, *P < 0.05), which could be prevented by pretreatment with Compound 15 (10 mg/kg, intraperitoneally, n = 6). (B) Shown is the force necessary to elicit paw withdrawal in Toll-like receptor 4 (Tlr4) wild-type and Tlr4 knockout mice. Systemic M3G (25 mg/kg, intraperitoneally) produced robust tactile hyperalgesia in Tlr4 wild-type mice (n = 6, *P < 0.05). Tlr4 knockout mice failed to display a decrease in paw withdrawal force following systemic M3G (n = 6).