BACKGROUND AND PURPOSE: Cannabinoid-2 (CB(2)) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/-)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB(2) receptors in (+)AM1241 and L768242 protean agonism. EXPERIMENTAL APPROACH: Pharmacological profiles of CB(2) receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB(2)) or rat (rCB(2)) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)], followed by extensive washing. KEY RESULTS: In cell lines expressing either hCB(2) or rCB(2) receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 [5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol] was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB(2) receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration. CONCLUSIONS AND IMPLICATIONS: These results show that (+)AM1241 and L768242 are protean agonists at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB(2) receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB(2) receptors.