L-768242 (GW-405,833) is a potent and selective partial agonist for the cannabinoid CB2 receptor with marked anti-inflammatory and anti-hyperalgesic activity in high doses. L-768242 suppresses pathological pain in preclinical models without unwanted central side effects of CB1 agonists. L-768242 dose-dependently reversed established mechanical allodynia in models of neuropathic (i.e. partial sciatic nerve ligation (PSNL) model) and inflammatory (i.e. complete Freund's adjuvant (CFA) model) pain. Despite substantial penetration to the CNS L-768242 did not produce cannabimimetic deficits below doses of 100 mg/kg i.p. Anti-allodynic efficacy of L-768242 was opioid-independent as systemic administration of naltrexone did not block the anti-hyperalgesic or antinociceptive effects of L-768242. In in vitro studies, L-768242 was reported to behave as a partial agonist at human CB2 receptors and, alternately, a potent inverse agonist at both human and rat CB2 receptors and a weak agonist at rat CB1 receptors. L-768242 was suggested to act as a non-competitive CB1 antagonist as L-768242 non-competitively antagonized CP55,940-induced adenylyl cyclase activity, ERK1/2 phosphorylation, PIP2 signaling and CB1 internalization in vitro in HEK cells transfected with CB1 and showed a complex, time-dependent effect on arrestin recruitment in CHO cells. Anti-allodynic efficacy of L-768242 is CB1-dependent but does not seem to involve engagement of the CB1 receptor’s orthosteric site.