Non-cannabinoid CB1, non-cannabinoid CB2 antinociceptive effects of several novel compounds in the PPQ stretch test in mice

The analgesic and anti-hyperalgesic effects of cannabinoid- and vanilloid-like compounds, plus the fatty acid amide hydrolase (FAAH) inhibitor Cyclohexylcarbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597), and acetaminophen, were evaluated in the phenyl-p-quinone (PPQ) pain model, using different routes of administration in combination with opioid and cannabinoid receptor antagonists. All the compounds tested produced analgesic effects. Delta9-tetrahydrocannabinol (Δ9-THC) and ®-(+)-arachidonyl-1′-hydroxy-2′-propylamide (®-methanandamide) were active by three routes of administration: i.p., s.c. and, p.o. Δ9-THC produced ED50s of 2.2 mg/kg (0.3–15.6) i.p., 9 mg/kg (4.3–18.9) s.c., and 6.4 mg/kg (5.5–7.6) p.o. Similarly, ®-methanandamide yielded ED50s of 2.9 mg/kg (1–8) i.p., 11 mg/kg (7–17) s.c., and 11 mg/kg (0.9–134) p.o. N-vanillyl-arachidonyl-amide (arvanil) was active by two routes, producing ED50s of 4.7 mg/kg (3.0–7.4) s.c. and 0.06 mg/kg (0.02–0.2) i.p. Palmitoylethanolamide, URB597, and acetaminophen were active i.p., resulting in ED50s of 3.7 mg/kg (3.2–4.2), 22.9 mg/kg (11.1–47.2), and 160 mg/kg (63–405), respectively. None of the cannabinoid or opioid receptor antagonists tested blocked the compounds evaluated, with two exceptions: the antinociceptive effects of Δ9-THC and URB597 were completely blocked by SR141716A, a cannabinoid CB1 receptor antagonist. Western immunoassays performed using three opioid receptor antibodies, a cannabinoid CB1 receptor antibody and a transient receptor potential vanilloid type 1(TRPV1) receptor antibody, yielded no change in receptor protein levels after short-term arvanil, ®-methanandamide or Δ9-THC administration. These data suggest that all the compounds tested, except Δ9-THC and URB597, produced analgesia via a non-cannabinoid CB1, non-cannabinoid CB2 pain pathway not yet identified.