Despite its beneficial effects against pain, morphine use is accompanied by adverse effects such as constipation, nausea, vomiting, respiratory depression, and potential dependence on the drug.  A research team led by Alain Eschalier, Director of Inserm Unit 1107, Neuro-Dol, in Clermont Ferrand, has just shown that it is possible to separate these two types of effects, and retain the desired analgesic effect without the adverse effects. These results are published in the 17 December 2013 issue of Nature Communications.

3D visualization of morphine’s receptor when it is associated with its antagonist  © Kobilka Lab

The beneficial and adverse effects of morphine and other opiate drugs depend on the same receptor, the mu receptor. To separate them, the researchers worked on proteins located downstream of the receptor. They chose TREK-1, a channel that inhibits neuronal activity and is known from previous work to be involved in pain.

In the present study, the research team showed, using mice, that this channel is involved in the analgesic effect of morphine without any role in its adverse effects. Indeed, when the gene is deleted in mice, the analgesic effect of morphine tested in clinical pain models (post-operational type pain, for example) is reduced.

“The TREK-1 channels are essential for the analgesic effect of morphine, but are not involved in its adverse effects, since neither constipation, respiratory depression, nor physical dependence is changed in animals in which they have been deleted.

Direct activation of these channels may thus lead to a morphine-type analgesia without inducing the side-effects associated with this type of drug,” concludes Alain Eschalier, last author of the study.

The team is currently working on the synthesis of new TREK-1-activating drugs with members of the Analgesia Institute (a public-private partnership).