Background and purpose:  Pharmacological analysis of synergism or functional antagonism between different receptors commonly assumes that interacting receptors are located in the same cells. We have now investigated the distribution of α‐adrenoceptors, β‐adrenoceptors and cannabinoid‐like (GPR55) receptors in the mouse arteries.

Experimental approach:  Fluorescence intensity from vascular tissue incubated with fluorescent ligands (α₁‐adrenoceptor ligand, BODIPY‐FL‐prazosin, QAPB; β‐adrenoceptor ligand, TMR‐CGP12177; fluorescent angiotensin II; a novel diarylpyrazole cannabinoid ligand (Tocrifluor 1117, T1117) was measured with confocal microscopy. Small mesenteric and tail arteries of wild‐type and α_1B/D‐adrenoceptor‐KO mice were used.

Key results:  T1117, a fluorescent form of the cannabinoid CB₁ receptor antagonist AM251, was a ligand for GPR55, with low affinity for CB₁ receptors. In mesenteric arterial smooth muscle cells, α_1A‐adrenoceptors were predominantly located in different cells from those with β‐adrenoceptors, angiotensin receptors or cannabinoid‐like (GPR55) receptors. Cells with β‐adrenoceptors predominated at arterial branches. Endothelial cells expressed β‐adrenoceptors, α‐adrenoceptors and cannabinoid‐like receptors. Only endothelial α‐adrenoceptors appeared in clusters. Adventitia was a rich source of G protein‐coupled receptors (GPCRs), particularly fibroblasts and nerve tracts, where Schwann cells bound α‐adrenoceptor, β‐adrenoceptor and CB‐receptor ligands, with a mix of separate receptor locations and co‐localization.

Conclusions and implications:  Within each cell type, each GPCR had a distinctive heterogeneous distribution with limited co‐localization, providing a guide to the possibilities for functional synergism, and suggesting a new paradigm for synergism in which interactions may be either between cells or involve converging intracellular signalling processes.

This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00685.x