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The present study examined physical and functional interactions between these receptors in a heterologous expression system and in primary human ocular cells.<\/jats:p><jats:p><jats:bold>Experimental approach:\u2002<\/jats:bold>Physical interactions between CB<jats:sub>1<\/jats:sub>receptors and \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptors were assessed using bioluminescence resonance energy transfer (BRET). Functional interactions between these receptors were evaluated by examining receptor trafficking, as well as extracellular signal\u2010regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) signalling.<\/jats:p><jats:p><jats:bold>Key results:\u2002<\/jats:bold>Physical interactions between CB<jats:sub>1<\/jats:sub>receptors and \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptors were demonstrated using BRET. In human embryonic kidney (HEK) 293H cells, co\u2010expression of \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptors tempered the constitutive activity and increased cell surface expression of CB<jats:sub>1<\/jats:sub>receptors. Co\u2010expression altered the signalling properties of CB<jats:sub>1<\/jats:sub>receptors, resulting in increased G\u03b1<jats:sub>i<\/jats:sub>\u2010dependent ERK phosphorylation, but decreased non\u2010G\u03b1<jats:sub>i<\/jats:sub>\u2010mediated CREB phosphorylation. The CB<jats:sub>1<\/jats:sub>receptor inverse agonist AM251 (N\u2010(piperidin\u20101\u2010yl)\u20105\u2010(4\u2010iodophenyl)\u20101\u2010(2,4\u2010dichlorophenyl)\u20104\u2010methyl\u20101H\u2010pyrazole\u20103\u2010carboxamide) attenuated \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptor\u2010pERK signalling in cells expressing both receptors, while the CB<jats:sub>1<\/jats:sub>receptor neutral antagonist O\u20102050 ((6aR,10aR)\u20103\u2010(1\u2010methanesulfonylamino\u20104\u2010hexyn\u20106\u2010yl)\u20106a,7,10,10a\u2010tetrahydro\u20106,6,9\u2010trimethyl\u20106H\u2010dibenzo[b,d]pyran) did not. The actions of AM251 and O\u20102050 were further examined in primary human trabecular meshwork (HTM) cells, which are ocular cells endogenously co\u2010expressing CB<jats:sub>1<\/jats:sub>receptors and \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptors. In HTM cells, as in HEK 293H cells, AM251 but not O\u20102050, altered the \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptor\u2013pERK response.<\/jats:p><jats:p><jats:bold>Conclusion and implications:\u2002<\/jats:bold>A complex interaction was demonstrated between CB<jats:sub>1<\/jats:sub>receptors and \u03b2<jats:sub>2<\/jats:sub>\u2010adrenoceptors in HEK 293H cells. As similar functional interactions were also observed in HTM cells, such interactions may affect the pharmacology of these receptors in tissues where they are endogenously co\u2010expressed.<\/jats:p><jats:p>This article is part of a themed issue on Cannabinoids. 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