Abstract
Cannabinoid CB(2) agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB(2) agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB(1) (SR141716) and CB(2) (SR144528) antagonists. AM1710 (0.1-10mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB(2) agonist (R,S)-AM1241 (1mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1mg/kg i.p.) dose of AM1710 was blocked selectively by the CB(2) antagonist SR144528 (6mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5mg/kg i.p.) was blocked by either SR144528 (6mg/kg i.p.) or SR141716 (6mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB(2)-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB(1)-mediated antinociceptive effects of this compound may be attributable to peripheral CB(1) activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.