Light-activated opioid painkiller may work without dangerous side effects

by Weill Cornell Medical College

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Opioid painkillers are some of the strongest analgesic medicines, but they are also the riskiest owing to a range of side effects, including addiction. An experimental opioid painkiller designed to be reversibly switched on and off with different light frequencies, keeping its action local and out of the brain, may eliminate the dangerous side effects of current opioids, according to a study led by Weill Cornell Medicine and University of Pennsylvania investigators. The findings herald a broad new approach for targeting medicines more precisely and effectively.

The investigators, whose results are published Oct. 15 in Cell, engineered a morphine-based compound called AM-3 that changes its shape in response to light in a certain frequency range. This conformational change alters AM-3's degree of engagement with the mu-opioid receptor, the principal target of opioid painkiller drugs.

The researchers showed that with this light-switching or "photopharmacology" approach they could activate AM-3's painkilling effect only where needed, allowing substantial pain relief without side effects in multiple preclinical pain models, including cancer pain models.

"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," said study co-senior author Dr. Joshua Levitz, a professor of biochemistry and biophysics at Weill Cornell Medicine.

The study was a collaboration with the laboratory of Dr. Dirk Trauner, the Penn Integrates Knowledge Professor of Chemistry & Pharmacology in the University of Pennsylvania School of Arts & Sciences and the Perelman School of Medicine.

Dr. Vsevolod Katritch, professor in the department of quantitative and computational biology, and Dr. Cornelius Gati, associate professor of biology, both at the USC Dornsife College of Letters, Arts and Sciences, were also major contributors to the work.

Postdoctoral researcher Dr. Luca Posa and former doctoral student Dr. Giovanna Romano at Weill Cornell Medicine; postdoctoral researcher Dr. Xiang Ji at the University of Pennsylvania; and doctoral candidate Saif Khan and postdoctoral researcher Dr. Antonina Nazarova at the USC Dornsife College of Letters, Arts and Sciences are co-first authors of the study.

Tackling the downsides of opioids

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 column, peripheral nerves and gut. These compounds can be very potent painkillers, but their body-wide 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. Last year, according to the Centers for Disease Control and Prevention, more than 40,000 Americans died from overdoses involving opioids.

"It would be terrible if we would deprive people suffering from debilitating pain of opioids, because they're too important and effective for that," said Trauner. "Yet, you want to make them safer, and that's our main goal here: that we make them safer by controlling them with light in the periphery."

Eliminating or at least greatly reducing opioid painkillers' side effects would mean targeting their activity very selectively to the neurons or nerve fibers where they are needed. In the study, the team demonstrated a solution to this problem that makes use of azobenzenes, organic compounds that can change their shape when exposed to certain light frequencies, and can do so stably and reversibly for many on/off cycles.

Using electron microscopy and other structural biology tools, 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 more weakly when in a shape induced by blue light.

Advancing toward the clinic

The team showed that in preclinical models, including models of bone cancer pain and visceral pain, injecting AM-3 and then briefly illuminating the pain site with UV light to induce AM-3's high-potency shape yielded a morphine-like painkilling effect at that site—with reduced or no signs of tolerance, constipation and other side effects. AM-3 cannot cross into the brain easily, which also helps minimize brain-based side effects such as addiction and respiratory suppression.

The investigators hope to take their approach through further preclinical development and ultimately to clinical trials. A potential hurdle is AM-3's requirement for ultraviolet light—which can damage eyes and skin—to induce its high-potency shape. But the researchers are working on successor molecules that are switchable with safe, visible light frequencies.

"Our goal is to make them sensitive toward long wavelengths like red light, which can deeply penetrate skin and tissue," Trauner said. "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."

"The idea of light-switched receptor activators has been out there for 15 years or so, but I think with these results we've now taken it farther than anyone else," he said.

Publication details

Luca Posa et al., An opioid efficacy switch for reversible optical control of analgesia, Cell (2026). DOI: 10.1016/j.cell.2026.09.042

Journal information: Cell

Key medical concepts

Analgesia

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Clinical pharmacologyCommon illnesses & Prevention Provided by Weill Cornell Medical College Who's behind this story?

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