NIH-Funded Scientists Discover Clues to Safer Painkillers

NIH-Funded Scientists Discover Clues to Safer Painkillers

Research funded by the National Institute on Drug Abuse (NIDA) shows that the mechanism of medically used opioids, such as morphine and oxycodone, has not been fully understood.

NIDA is a division of the National Institutes of Health (NIH).

The discovery could be good news for millions of patients who need the painkilling power of opioids, but who are at risk of dependence, addiction and other unwanted side effects.

It would also be a relief for countless physicians feeling forced to cut back on opioid prescriptions, without viable alternatives to manage patient pain.

Conventional wisdom holds that medical opioids like morphine and hydrocodone interact on the same neuron surface receptors in our brains and bodies as those used by "endogenous" - meaning naturally produced - opioids that are produced naturally in the brain. These natural opioids include endorphins, the well-known "feel-good" hormone activated by exercise. It was named by combining the words "endogenous" and "morphine." There are other natural opioids that create other kinds of effects.

The new research has discovered that medically used opioids not only bind to the same neuron surface receptors as endogenous opioids, but also to receptors inside the neurons. This simple-sounding discovery, says the NIH, could actually lead to new painkillers that don't carry the same risky side effects of dependence and addiction.

"We were surprised to see that drugs such as morphine activate opioid receptors in a location at which naturally occurring opioids do not," said Dr. Mark von Zastrow, senior author of the study.

How opioids really work

The research employed a novel molecular probe called a "nanobody" that generates a fluorescent signal when neurons are activated. This enabled the scientists to track chemicals as they moved through cells and responded to stimuli.

In addition to discovering that medical opioids interacted inside the receptors and not just on the surface, the researchers also learned the mechanisms of why some opioids are stronger than others, work faster or last longer.

The new information provides important clues to the how and why of undesired side effects of opioid medicines. And it suggests new avenues for designing agents that do not produce addiction or other adverse effects associated with the current range of opioids, the study said.
"This ground-breaking study has uncovered important distinctions between the opioids that our brain makes naturally and therapeutic opioids that can be misused," said NIDA Director Nora D. Volkow, M.D. "This information can be mined to better understand the potential adverse actions of medically prescribed opioids and how to manipulate the endogenous system to achieve optimal therapeutic results without the unhealthy side effects of tolerance, dependence, or addiction."

Any such drugs are a long way off – possibly years from now. But it's encouraging to learn that progress is being made, and by scientists funded by our tax dollars.

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