The search for a drug to replace morphine—a highly effective pain reliever but one that is associated with a variety of troublesome side effects—may be greatly accelerated thanks to a recent discovery by scientists at Albany Medical College and the state Wadsworth Center Laboratories.

In a study just published in the current edition of Nature Neuroscience, scientists from both organizations said that their experiments demonstrated that a specific family of proteins in the brain known as cytochrome P450 epoxygenases play an essential role in spurring morphine’s pain-relieving actions. These enzymes were not previously thought to play such a role.

The scientists said their research brings them a step closer to the development of a new class of pain-relieving drugs that may not have the detrimental side effects of morphine, which include constipation, respiratory distress and even addiction.

“The more we can understand about how morphine is processed in the brain, and what specifically make it an effective pain reliever, the closer we position ourselves to being able to develop equally effective drugs, but ones that might have fewer side effects,” said Lindsay B. Hough, Ph.D, professor and associate director of the Center for Neuropharmacology and Neuroscience at Albany Medical College, one of the study’s two principal authors. The other author was Xinxin Ding, Ph.D., chief, Laboratory of Molecular Toxicology at the New York State Department of Health’s Wadsworth Center. Scientists from Rensselaer Polytechnic Institute in Troy and the University of Rochester collaborated on the research, which was supported by grants from the National Institutes of Health and the United States Public Health Service.

In earlier studies at Albany Medical College, Hough and his team discovered improgan, a novel pain-relieving agent that doesn’t have the side effects of morphine but which—thus far—had proved to be impractical since it must be injected directly into the brain to be effective. In this earlier research, Hough and his team suspected that P450 played an important role in the way it interacted with improgan to alleviate pain. He and his team wondered if it would play a similar role with morphine and their latest research confirmed that it does.

In a series of experiments using mice and rats, the team of scientists proved that when P450 epoxygenases were blocked—either by drug inhibitors or by gene manipulation methods—there was a significant loss in the pain-relieving properties of the morphine.

“Discovery of the significance of epoxygenase enzymes within the brain’s pain-relieving pathways requires many additional experiments to identify the specific cells, circuits, and molecules which may be critical for pain relief,” noted Hough. “But now that we know these proteins are essential in the brain’s pain-relieving response, there is the potential to eventually produce new kinds of pain-relieving drugs that may not cause the negative side effects.”

Co-first authors on the study were Jennie Conroy, pre-doctoral fellow at Albany Medical College, and Cheng Fang, Ph.D., post-doctoral fellow at Wadsworth. Other upstate collaborators on the study included Mark P. Wentland, Ph.D., Rensselaer Polytechnic Institute, Troy, NY; and Jean M. Bidlack, Ph.D., University of Rochester, Rochester, NY. 

At Albany Medical College, one of the nation’s oldest medical schools, basic research scientists work to facilitate discoveries that translate into medical innovations at patients’ bedsides. NIH-funded scientists are conducting research in many exciting areas including infectious disease, biodefense, addiction, cancer, pain, and more.

Source: Albany Medical Center