Morphine and other opioids work wonders for pain. Unfortunately, their effectiveness declines over time while their addictiveness grows, meaning patients need the drug even as it affords them less and less relief. But new research into the cellular workings of opioids offers a promising new pathway to improved pain relief–without the addiction–by triggering one receptor and blocking another.
Medicinal chemist Philip Portoghese of the University of Minnesota and his colleagues began by studying two of the four major opioid receptors in the cells of the central nervous system. Each bears the name of a Greek letter and the chemists focused on the Mu and Delta receptors. Previous research had shown that drugs that linked up with Mu receptors lasted longer with less addiction when combined with drugs that blocked Delta receptors. But it was not known whether the two channels worked separately or in concert to improve the overall effect. So Portoghese and his colleagues built a drug that triggered the Mu receptor while blocking the Delta receptor–dubbed MDAN, for Mu Delta agonist antagonist. They administered various versions of the drug to mice and then tested their sensitivity to pain by focusing a hot light on their tails and recording the time it took the animals to move them. The MDAN drug proved roughly 50 times more effective than morphine in blocking pain, the researchers report in this week’s online edition of the Proceedings of the National Academy of Sciences.