This figure shows the resolution at the atomic level of the tetracycline antibiotic bound to the EphB1 receptor. Photo credit: UT Southwestern Medical Center
Three decades-old antibiotics given together can block a type of pain caused by nerve damage in an animal model, researchers at UT Southwestern report. The finding, published online today in PNAS, could provide an alternative to opioid-based pain relievers, the addictive prescription drugs that are responsible for an epidemic of abuse in the United States.
Chronic pain affects over 100 million Americans, and a quarter of them experience pain every day. This burden costs an estimated $ 600 billion in lost wages and medical expenses each year. In many of these patients – for example, those with cancer, diabetes, or trauma – the pain is neuropathic, which means that it is caused by damage to nerves that are sensitive to pain.
For the treatment of chronic pain, opioid pain medication prescriptions have increased exponentially since the late 1990s, leading to an increase in abuse and overdoses. Despite the desperate need for safer pain relievers, it typically takes more than a decade and more than $ 2 billion to develop a new prescription drug, according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, MD , Dr. Associate professor for anesthesiology and pain therapy at the UTSW.
Looking for an alternative to opioids, Kandil and her colleagues from UT Southwestern – including Hesham A. Sadek, Ph.D., professor of internal medicine, molecular biology and biophysics; Mark Henkemeyer, Ph.D., Professor of Neuroscience; Mahmoud S. Ahmed, Ph.D., internal medicine instructor; and Ping Wang, Ph.D., a postdoctoral fellow, investigated the potential of drugs that have already been approved by the Food and Drug Administration (FDA).
The team focused on EphB1, a protein on the surface of nerve cells that Henkemeyer and his colleagues discovered during his postdoctoral studies almost three decades ago. Research has shown that this protein is key to generating neuropathic pain. Mice genetically engineered to remove all of the EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting that EphB1 is a target for pain reliever drugs. Unfortunately, no known drugs inactivate EphB1.
Ahmed explored this angle further, using computer models to scan a library of FDA-approved drugs to test that their molecular structures were in the right shape and chemistry to bind to EphB1. Your search returned three tetracyclines, members of a family of antibiotics that had been used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, says Ahmed.
To investigate whether these drugs can bind to and inactivate EphB1, the team combined the protein and these drugs in Petri dishes and measured the activity of EphB1. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang mapped the structure of EphB1 with chlortetracycline and showed that the drug fits snugly into a pocket in the protein's catalytic domain, a key part required for EphB1 to function.
In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted responses to painful stimuli such as heat or pressure, with the triplet being more effective at lower doses than either drug individually. When the researchers examined the brain and spinal cord of these animals, they confirmed that EphB1 had been inactivated on the cells of these tissues, the likely cause of their pain resistance. A combination of these drugs could potentially relieve pain in humans, the next step in this research, says Kandil.
"If we don't find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic," she says. "This study shows what can happen when you bring together scientists and doctors with different experiences and backgrounds. We're opening the window to something new."
The post-operative patch releases non-opioid pain relievers directly to the wound
Mahmoud S. Ahmed et al., "Identification of Tetracycline Combinations as EphB1 Tyrosine Kinase Inhibitors for the Treatment of Neuropathic Pain", PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2016265118
UT Southwestern Medical Center
Three long-standing antibiotics could provide an alternative to addictive opioid pain relievers (2021, Feb.22).
accessed on February 22, 2021
This document is subject to copyright. Apart from fair treatment for the purpose of private study or research, no
Part may be reproduced without written permission. The content is provided for informational purposes only.