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.
But MDAN still paled in comparison to drugs designed purely to stimulate the mu receptor, which exhibit more than 100 times the pain blocking potential of morphine. The MDAN drugs had another benefit, however: the mice did not develop any dependence. Mice given morphine and then abruptly cleared of it showed severe agitation, jumping roughly 100 times in a 10 minute span, and mice given just the mu agonist showed similar agitation, jumping between 83 and 29 times over the same span, depending on the formulation. The mice given MDAN showed hardly any agitation at all, averaging less than one jump.
The mice also failed to develop any tolerance for MDAN--that is, the drug worked just as well at the beginning of the experiment in alleviating pain as it did at the end. "It's been a perennial problem with morphine that upon chronic administration you get a tolerance, you're going to have to raise the dose to get the same effect over time," Portoghese says. "When you're occupying the mu receptor with an agonist and the delta receptor with an antagonist, that doesn't happen."
"The mu delta receptor dimer is the signaling unit that gives rise to tolerance and physical dependence," Portoghese notes. Perhaps MDAN can provide help for pain and insights into addiction at the same time. What a relief that would be.