Effects of THC on IP acid–induced stretching, facial grimace, rearing, and nesting behaviors in male and female mice. Abscissae: dose of THC delivered subcutaneously in milligrams per kilogram (log scale). Ordinates: number of stretches (A), grimace score (B), number of rears (C), and nesting expressed as percent maximum nestlet consolidation (D). Each point shows ±S.E.M. for 12 mice (six male, six female). Filled symbols indicate a significant difference from vehicle (Veh) as determined by repeated-measures one-way ANOVA and Dunnett’s post hoc test for parametric data (A, C, and D) or by Friedman’s and Dunn’s post hoc test for nonparametric data (B), P < 0.05. Results of ANOVA and power analysis data for each panel are shown in Table 1.

Effects of MAGL-selective inhibitors MJN110 and JZL184 on IP acid–induced stretching, facial grimace, rearing, and nesting behaviors in male and female mice. Abscissae: doses of MJN110 or JZL184 delivered subcutaneously in milligrams per kilogram (log scale). Ordinates: number of stretches (A), grimace score (B), number of rears (C), and nesting expressed as percent maximum nestlet consolidation (D). Other details as in Fig. 2.

Effects of dual MAGL and FAAH inhibitors JZL195 and SA57 on IP acid–induced stretching, facial grimace, rearing, and nesting behaviors in male and female mice. Abscissae: doses of JZL195 or SA57 delivered subcutaneously in milligrams per kilogram (log scale). Ordinates: number of stretches (A), grimace score (B), number of rears (C), and nesting expressed as percent maximum nestlet consolidation (D). Other details as in Fig. 2.

Effects of FAAH-selective inhibitors URB597 and PF3845 on IP acid–induced stretching, facial grimace, rearing and nesting behaviors in male and female mice. Abscissae: doses of URB597 and PF3845 delivered subcutaneously in milligrams per kilogram (log scale). Ordinates: number of stretches (A), grimace score (B), number of rears (C), and nesting expressed as percent maximum nestlet consolidation (D). Other details as in Fig. 2.

Effects of endocannabinoid catabolic enzyme inhibitors and THC on nesting and locomotor behaviors in male and female mice in the absence of the IP acid noxious stimulus. Abscissae: doses of endocannabinoid catabolic inhibitors or THC in milligrams per kilogram. Doses of endocannabinoid catabolic enzyme inhibitors for locomotor studies were the highest tested in antinociception assays, whereas THC [inset in (B)] was tested across a range of doses. Ordinates: nesting expressed as percent maximum nestlet consolidation (A), and locomotor counts (B). Each point shows ±S.E.M. for 12 mice (six male, six female). Filled symbols in (A) and the asterisk in (B) inset indicate a significant difference from vehicle (Veh) as determined by repeated-measures one-way ANOVA and Dunnett’s post hoc test, P < 0.05. Results of ANOVA and power analysis data for each panel are shown in Table 1.

Drug profiles for comparison of potency to produce antinociceptive effects on IP acid–stimulated and IP acid–depressed behaviors vs. general behavioral disruption. Abscissae: drug dose in milligrams per kilogram (log scale). Boxed letters (S, G, R, N) denote the dose range over which each drug significantly attenuated IP acid–induced stimulation of stretching (S) or facial grimace (G) or IP acid–induced depression of rearing (R) or nesting (N). In each panel, boxes for pain-stimulated behaviors (PSB) and pain-depressed behaviors (PDB) are shown above and below the dose axis, respectively. The gray zone at the right edge of panels for THC and PF3845 shows doses that produced motor disruption in assays of nesting and/or locomotion in the absence of the IP acid noxious stimulus. For the other drugs, no tested dose altered nesting or locomotion in the absence of the noxious stimulus, and no gray zone is indicated. The test compounds for inhibition of the two main endocannabinoid degradative enzymes, MAGL and FAAH, are organized by their selectivity, going from MAGL-selective to FAAH-selective, as indicated by the selectivity arrows on the right.