The opioid epidemic has been called the “deadliest drug crisis in American history” by the New York Times. Overdoses claim the lives of more than 90 Americans each day, and about two million people battle substance abuse disorders stemming from prescription opioids, according to the National Institute on Drug Abuse.

As healthcare professionals, pharmaceutical companies, patients and families grapple with the crisis, researchers are rushing to design safer opioids.

Finding a less addictive solution

According to Jennifer Whistler, associate director of the UC Davis Center for Neuroscience, drug development is headed in the wrong direction. Trends favor synthetic opioids that may mitigate side-effects, such as respiratory failure, while overlooking the larger issues of tolerance and addiction.

“Developing an orally available drug which provides pain relief and reward with reduced respiratory suppression and constipation does nothing to prevent tolerance or dependence,” said Whistler, professor of Physiology and Membrane Biology. “And there is significant evidence that such drugs could be even more addictive.”

Oxycodone, morphine, fentanyl and other prescription opioids all miss the mark for the same underlying reason, according to Whistler, who is trying to inform the development of a less addictive prescription opioid therapy. She’s launching an addiction research program at the Center for Neuroscience. Her goal: mitigate addiction and tolerance by designing an opioid therapy that mimics the body’s natural pain reliever, endorphin.

Whistler tests a mouse's ability to learn new rules. Mice who experience opioid withdrawal are less able to learn new rules. In this experiment, the red light mimics darkness, allowing Whistler to study the mice's behavior at night. David Slipher/UC Davis

The science behind addiction

Both prescription opioids and endorphins bind to the same receptors—in the brain, spinal cord and digestive tract—the opioid receptors. One can think of these receptors like light switches. Experience an injury, and endorphins are released to mask the pain. The endorphin binds to opioid receptors, which flips the switch “on” by sending a signal to a molecule called G-protein.

Activation of the G-protein functions as a soothing light for the cell and provides pain relief and a sense of well-being or reward. However, over time, endorphin switches off these G-protein effects by signaling to another molecule called arrestin, which turns off the light.

Prescription opioid painkillers work similarly but all of them are biased towards G-protein signaling, amplifying pain relief and reward effects. They provide the cell with soothing light, but because they don’t signal to arrestin, the light never switches off.

Since they can’t use the light switch to turn down the light, with repetitive opioid use, cells instead adapt and grow accustomed to that soothing light. It’s as if they’re wearing sunglasses. And because they are wearing sunglasses, in order to achieve the same pain relief and reward as before, more light—a higher opioid dosage—is needed. Furthermore, when the light is taken away, for example when the prescription runs out, the cells are in the dark but still wearing sunglasses.

“We hypothesize that the changes the cells make—this action of shopping for dark sunglasses—is responsible for tolerance and dependence,” Whistler said, noting that tolerance causes users to increase dosages for pain relief which in turn increases the need for sunglasses in a perpetual cycle.

Arrestin signaling, the key to prevention

Whistler believes efficient arrestin signaling is key to preventing tolerance and addiction. So why don’t drug manufacturers simply produce opioids that signal both to G protein and arrestin like the endorphins do?

According to Whistler, many researchers link arrestin signaling to negative side-effects like respiratory suppression. By dampening arrestin signaling, they aim the development of new opioid drugs towards reducing respiratory failure and death.

But while mitigating the respiratory side effects might increase the therapeutic window for legitimate uses of these

Opioid overdoses claim the lives of more than 90 Americans each day, and about two million people battle substance abuse disorders stemming from prescription opioids, according to the National Institute on Drug Abuse. Wkimedia Commons

drugs, it does nothing to address the underlying cause of the opioid epidemic—the transition from legitimate use to dependence and addiction.

Rather than develop G-protein biased drugs, Whistler wants to create a balanced opioid that more closely mimics the way endorphins in the body switch pain relief on and off.

“What we need to do is focus on identifying something more similar to what nature gave us,” Whistler said.

Taking a unorthodox approach to curb dependence

The opioid methadone behaves most like endorphin. Commonly used to treat heroin addiction, methadone signals strongly to both G-protein and arrestin, unlike every other opioid used to treat pain.

But methadone is problematic as a pain medication because it has a long half life and its respiratory suppression effects often last longer than its pain relief effects. Consequently, doubling down on a dosage can prove deadly for a patient.

Whistler wants to use methadone differently. In a 2005 Current Biology paper, she reported the creation of an opioid drug cocktail consisting of morphine, to signal to G protein for pain relief, and a trace amount of methadone to signal to arrestin. In experimental trials, rats dosed with only morphine developed a profound tolerance and dependence by day five. Rats treated with the drug cocktail, containing the same amount of morphine for pain relief, didn’t develop tolerance or dependence.

“With the right clinical partner, we could develop a formulation that mixes one of the biased prescription opioids and methadone,” Whistler said. “The first opioid kills the pain while the tiny dose of methadone gives the cocktail a nudge towards balance.”

While the study didn’t gain traction in the field at the time of its publication, Whistler hopes a renewed public interest in the opioid epidemic will spur development of new therapies that buck the traditional approach to opioid drug design. As the Center for Neuroscience’s associate director, she sees a new opportunity to explore these research avenues with her UC Davis colleagues and hopes to kindle interest in her methodology.

A new home at UC Davis

Whistler joined UC Davis and the Center for Neuroscience in November. A UC Davis alumna, she received a B.S. in Genetics in 1987 and later earned a Ph.D. in Cell and Molecular Biology from UC Berkeley. She later worked as a professor and principal investigator at UC San Francisco, in the Neurology Department and at the Ernest Gallo Clinic and Research Center. She ran programs studying biased signaling in several receptor families including opioid, dopamine and cannabinoid receptors.

Working with Center for Neuroscience director Kim McAllister, Whistler hopes to create a shared vision for the center’s faculty and researchers who come from disciplines across the field of brain science.

In addition to the neurobiology of addiction, research at the Center for Neuroscience includes sensory physiology, human perception, memory and the nature of consciousness, among many other areas. Whistler’s job is to find the connections that unite all the researchers.

“People here are studying many things that might be relevant to addiction, like decision-making and early brain development,” Whistler said. “My goal is to connect the dots and build a program in addiction biology that spans many disciplines and brings new talent into this field.”