Using a newly developed X-ray source, scientists have revealed how a new type of pain-reliever works. By bonding to the same neuroreceptors that morphine does, but without the accompanying physical dependence makes for a potentially new way of treating pain.
“If you know how the binding physically works, you can design molecules to target the specific receptor sites and generate specific responses,” said Vadim Cherezov, professor at the USC Dornsife College of Letters, Arts and Sciences and corresponding author on a paper about the research that was published online by Nature Structural & Molecular Biology on Feb. 16, 2015.
Opiate painkillers like oxycodone or morphine try to artificially release molecules, or “ligands,” called enkephalins, endorphins and dynorphins that bind to the four major receptors in the brain and spinal cord. The four major receptors are delta, kappas, mu and Nociceptin. The body naturally does this which regulates mood and pain. When it is done artificially, these drugs target the mu receptors. The problem is that although they relieve pain when targeting the mu receptors, their prolonged use caused a growing tolerance to the drugs and ultimately a physical dependence and addiction.
Previous research has shown that administering morphine with a chemical that simultaneously blocks delta receptors cuts down on those negative side effects. This has lead researchers to believe there must be a way to engineer a drug that interacts with both the mu and delta receptors in such a way that it would have all of the benefits of morphine but none of the drawbacks such as addiction and dependance.
Cherezov and his team focused on a molecule that is structurally similar to the body’s natural ligands, but which operates differently by activating mu receptors while blocking delta receptors.
“Drug abuse is the leading cause of injury-related deaths in the United States and opioid abuse cost the U.S. approximately $58 billion in 2007. The structural data are helping to provide new insight into the understanding of how the receptors work in our body, and the design of novel molecules that might help address this critical health issue,” said Raymond Stevens, co-author of the study and director of the Bridge Institute at USC Dornsife.
To figure out what a tiny biological structure looks like, scientists usually grow crystals of them and then blast those crystals with X-rays, piecing together a picture of what they look like based on the way that the X-rays bounce off of them. The way this used to be done was not sufficient in helping with the study so Cherezov and his team used a new technique that features a brighter X-ray free electron laser. While it might seem counterintuitive, blasting the crystals with a higher intensity but very short X-ray pulses allows Cherezov to use smaller crystals at near-body temperatures, rather than cryo-cooling them. The new process allows them to see undamaged protons. In lamen's terms, it helps their study to see how they can target the cells better. This is a breakthrough and from this research, new medications may be a reality that can help with pain and with no chance of addiction.