Ecstatic about RAVE

We are all naturally dependent on opioids for our emotional health, and some of us indulge in their recreational use. Both internally generated endorphins and drugs exert their action by interacting with specific membrane receptor proteins on neurons. Opioid painkillers, such as morphine, also exert their effect through the μ-opioid receptor (MOR). Use of morphine is hindered in the long-term by the development of tolerance to the painkilling effects of the drug. In contrast to the prevailing view, Whistler and colleagues provide in vivo evidence that endocytosis of MOR can reduce, rather than increase, the development of tolerance to morphine.

Opioid receptors belong to the large superfamily of G-protein-coupled receptors (GPCRs). The mechanisms for mediating the development of tolerance and dependence to morphine are controversial. The ability of MOR agonists to promote endocytosis of MOR is not related linearly to the agonist activity. The net amount of a signal that is transmitted to the cell is a function of both processes, a relationship termed 'relative activity versus endocytosis', or RAVE. Morphine has a high RAVE value because of an inability to promote endocytosis. Endorphins and other opiate drugs have similar signalling efficacies, but have lower RAVE values because they induce endocytosis.

Whistler and colleagues reasoned that if prolonged signalling at MOR contributes to the development of tolerance, then lowering the RAVE value by reducing that prolonged signalling would reduce the unwanted side effects. Consistent with this hypothesis, they showed that rats treated chronically with morphine plus the enkephalin, DAMGO (d-Ala²-MePhe⁴-Gly⁵-ol), which facilitates MOR endocytosis, had reduced development of analgesic tolerance compared with rats treated with morphine alone. The present study shows that MOR can dimerize, as seen with other GPCRs, and proposes that this dimerization is mechanistically important in influencing the endocytic properties of the receptor, thereby reducing the development of tolerance to morphine.

The current view that endocytosis of MOR contributes directly to tolerance by decreasing the number of functional receptors on the cell surface has discouraged drug discovery programmes from investigating new agonists to promote endocytosis. However, this study indicates that agonists that promote endocytosis of MOR might provide analgesics with improved tolerance profiles. In the meantime, administration of drugs that promote endocytosis of MOR with morphine might produce less tolerance than morphine alone.