Last year, more than 40,000 Americans died from overdoses involving opioids, according to the Centers for Disease Control and Prevention .
Opioid compounds, including morphine, codeine, and fentanyl, exert most of their effects by activating mu-opioid receptors, which are found throughout the brain and in the spinal cord, peripheral nerves, and gut. These compounds can be very potent painkillers, but their bodywide activity leads to side effects including constipation, tolerance (the need for higher and higher doses), addiction, and—potentially fatally—the suppression of brain signals that control breathing.
Eliminating or at least greatly reducing side effects would mean targeting the activity of opioid painkillers very selectively to the neurons or nerve fibers where they are needed.
In a new paper published in Cell , chemist and pharmacologist Dirk Trauner and collaborators at Weill Cornell Medicine and the University of Southern California present an experimental opioid painkiller designed to be reversibly switched “on” and “off” with different light frequencies to keep its action local and out of the brain. Their findings may eliminate the dangerous side effects that characterize current opioids.
“It would be terrible if we would deprive people suffering from debilitating pain from opioids, because they’re too important and effective for that,” says Trauner, a Penn Integrates Knowledge Professor in the School of Arts & Sciences and the Perelman School of Medicine . “Yet, you want to make them safer, and that’s our main goal here.”
The work builds on two decades of research in Trauner’s lab on controlling biology with light. In 2004, Trauner and colleagues at the University of California, Berkeley, used a synthetic azobenzene switch to turn the firing of neurons on and off with light.
The paper appeared months before a landmark study by Karl Deisseroth and colleagues that helped define and establish optogenetics, the use of light to control the activity of nerve cells—a field that was recognized with this year’s Nobel Prize in Physiology or Medicine . Trauner notes that the early history highlights the crucial role chemistry played in the field’s origins.
“The idea of light-switchable receptor activators has been around for 20 years or so, but I think these results represent a major step forward,” says study co-senior author Joshua Levitz , a professor of biochemistry and biophysics at Weill Cornell Medicine.
Using azobenzenes, organic compounds that can stably and reversibly change their shape when exposed to certain light frequencies, the team designed several morphine-azobenzene compounds that engage the mu-opioid receptor differently depending on the light to which they’ve been exposed.
One of these compounds, AM-3, worked just as they had hoped, activating the mu-opioid receptor strongly when in a shape induced by near-ultraviolet light but weakly when in a shape induced by blue light.
The researchers showed that with this “photopharmacology” approach, they could activate AM-3’s painkilling effect only where needed, allowing substantial pain relief without side effects such as tolerance or constipation in multiple preclinical pain models, including cancer pain models. AM-3 cannot cross into the brain easily, helping to minimize brain-based side effects such as addiction and respiratory suppression.
“We think this is a significant breakthrough not just for pain management but also for the general strategy of photopharmacology, which has a great many potential applications in biology and medicine,” says Levitz.
The teams hope to take their approach through further preclinical development and ultimately to clinical trials. The researchers are working on successor molecules that are switchable with safer light frequencies than ultraviolet light, which can damage eyes and skin.
“Next is to make them adaptable for humans,” says Trauner. “Our goal is to make them sensitive toward long wavelengths like red light, which can deeply penetrate skin and tissue. We need to improve the photochemistry, but we have some pretty good ideas on how to do this. In fact, we have some exciting preliminary results already.”
Weill Cornell Medicine contributed to this news release .
Dirk Trauner is the George A. Weiss University Professor and a Penn Integrates Knowledge Professor with joint appointments in the Department of Chemistry in the School of Arts & Sciences and the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine at the University of Pennsylvania.
Joshua Levitz is a professor of biochemistry and biophysics at Weill Cornell Medicine.
Other authors include Xiang Ji and Kenny Calderon-Godinez of Penn Arts & Sciences; Luca Posa, Giovanna R. Romano, Sheida Sharghi Moshtaghin, Anisul Arefin, Alberto J. Gonzalez-Hernandez, Ipsit Srivastava, and Kristen E. Pleil of Weill Cornell Medicine; Saif Khan, Antonina L. Nazarova, Gye Won Han, Saheem A. Zaidi, Zixin Zhang, Aaliyah S. Tyson, Mohsen Ranjbar, Vsevolod Katritch, and Cornelius Gati of the University of Southern California; Bruno Paz of New York University and the University of São Paulo; and Kanupriya Pande of Lawrence Berkeley National Laboratory.
This research was supported by the National Institutes of Health (grants R61/R33DA051529, R35GM150982, R01AT012075, R35GM153437, T32GM132081, and R36DA064987), the Rohr Family Research Scholar Award, the Monique Weill-Caulier Award, and the Charles H. Revson Fellowship.
Cell
Experimental study
Animals
An opioid efficacy switch for reversible optical control of analgesia
15-Oct-2026
L.P., G.R.R., V.K., D.T., and J.L. are inventors on a provisional patent application on the use of photoswitchable morphines for pain treatment.