FIGURE 3.

CB₁R mediates the TLR4/Δ9-THC–induced upregulation of IL-10 (A) TRPV1, CB₂R, and GRPR18 are not responsible for Δ9-THC–induced IL-10 upregulation in LPS-induced inflammation. n = 7 + 8 + 11 WT male mice, 7+7 Trpv1^−/− male mice, 4 + 8 Cnr2^−/− male mice, and 2 + 3 male and 2 + 3 female mice Gpr18^−/− (all 8–14 wk old). (B) Pharmacological blockade of CB₁R by SR141617 abrogates Δ9-THC–induced IL-10 upregulation in LPS-induced inflammation, whereas GPR119 and GPR55 blockade have no effect (8- to 11-wk-old WT male mice, n = 2 + 3 + 8+ 7 + 3 + 4 per group). **p < 0.01, ***p < 0.001, LPS + Δ9-THC–treated mice versus LPS + vehicle or LPS + Δ9-THC + SR141716. (C) CB1 antagonist SR141716 abrogates Δ9-THC–induced anti-inflammatory response in LPS-treated mice. Levels of IL-10 were quantified in plasma at t = 2, 4, and 6 h after LPS challenge (10-wk-old male, n = 5 per group). *p < 0.05, **p < 0.01, LPS + vehicle versus LPS + Δ9-THC and LPS + vehicle versus LPS + Δ9-THC + SR141617, two-tailed Mann–Whitney U test at each time point. (D) Among CB₁R agonists only Win5522-2, Hu-210, and NADA also upregulate IL-10 at t = 2 h after LPS challenge (9-wk-old male, n = 40). **p < 0.01, ***p < 0.001, LPS + vehicle versus LPS + CB₁R agonist. (E) σ1R blockade with BD1047 does not affect Δ9-THC–induced reduction in proinflammatory cytokines and IL-10 upregulation. Mice were pretreated with BD1047 IP 20 mg/,g 30 min before LPS (1 mg/kg i.v.) ± Δ9-THC (5 mg/kg i.v.). Levels of cytokines were quantified in plasma after at t = 2 h (8-wk-old female, n = 1 + 5 + 5 + 5 per group). *p < 0.05, **p < 0.01, ***p < 0.001, LPS + vehicle versus LPS + Δ9-THC or LPS + Δ9-THC + BD1047.