Figure 3. Nerve-injured mice defective in neuronal CB₂ receptor show increased self-administration of the CB₂ agonist JWH133 and a decrease in the antinociceptive effects of the drug.

Mice lacking CB₂ in neurons (Syn-Cre+), in monocytes (LysM-Cre+) or their wild-type littermates (Cre Neg) were food-trained in Skinner boxes (Food training, 5 days), subjected to partial sciatic nerve ligation (PSNL, day 0), catheterized and exposed to JWH133 (0.3 mg/kg/inf., days 7 to 18). Nociceptive sensitivity to heat (Plantar) and mechanical (von Frey) stimulation were measured before and after nerve injury (−1,3,6,18), anxiety-like behavior was evaluated at the end (day 19). (A) Syn-Cre+ mice showed increased active operant responding for JWH133 in the last sessions of the self-administration period (B) All mouse strains showed decreased heat nociception after JWH133 treatment, and Syn-Cre+ mice showed reduced effects of JWH133 on mechanical nociception. (C) Every mouse strain showed similar anxiety-like behavior after JWH133 self-administration. No significant differences were found between LysM-Cre+ and Cre Neg mice. N = 18–36 mice per group. Mean and error bars representing SEM are shown. Shaded areas represent drug self-administration. Stars represent comparisons vs. Cre Neg mice; crosses represent day effect. *p<0.05; **p<0.01; ***p<0.001.

Figure 3—figure supplement 1. JWH133 self-administration in mice lacking CB₂ in neurons or monocytes and their wild-type littermates and food-maintained operant training before nerve injury and drug self-administration.

(A) Mice lacking CB₂ in neurons (Syn-Cre+) mice showed increased active operant behavior directed to obtain high doses of the CB₂ agonist JWH133 (0.3 mg/kg/inf.). Operant responding for the CB₂ agonist was similar between mice lacking CB₂ in monocytes (LysM-Cre+) mice and their wild-type littermates (Cre Neg). (B) Syn-Cre+, LysM-Cre+ and Cre Neg mice developed similar operant behavior for food before the partial sciatic nerve ligation. N = 18–36 mice per group. Stars represent p<0.001 vs. Cre Neg.

Figure 3—figure supplement 2. Mice lacking CB₂ in Nav1.8+ peripheral neurons show unaltered JWH133 antinociceptive effects.

Intraperitoneal doses (i.p.) of 5 and 10 mg/kg JWH133 had similar effects on mechanical (A) and thermal (B) hypernociception of nerve-injured mice lacking CB₂ in peripheral neurons (Nav1.8-Cre+) and their wild-type littermates (Cre Neg). Mechanical and thermal thresholds before (Vehicle, 0 mg/kg, 7 days after surgery) and after the end of the treatments (After effect) also revealed similar sensitivity in both strains. White stars represent comparisons vs. Vehicle, Black stars vs. Sham. *p<0.05, ***p<0.001. N = 8–18 mice per group. Means and error bars represent SEM.