Opioid and cannabinoid receptors: friends with benefits or just close friends?

mu-Opioid (MOP) and cannabinoid CB1 receptors mediate overlapping pharmacological responses in clinically important areas such as drug abuse and pain management, and functional interactions between agonists at these receptors have long been recognized. In the present issue of this Journal, Rios and co-workers have provided the first strong evidence that the two receptors interact directly when coexpressed in the same cells. The authors report a close physical association between MOP and CB1 receptors and novel pharmacological interactions of MOP and CB1 agonists. They argue that MOP/CB1 heterodimer formation explains these interactions. If correct, the direct interaction of MOP and CB1 pharmacophores in a quaternary complex would provide real benefits by opening the potential for development of novel MOP/CB1 small molecules or new strategies for use of current ligands. However, a lot more evidence will be required before the heterodimer interpretation can be accepted. If it turns out that MOP and CB1 receptors do not readily form hetero-oligomers, the study by Rios and co-workers shows that they are still friends but there may be few benefits.