Light-Activated Opioid Relieves Pain in Mice Without Addiction Risks

Opioids are the strongest painkillers medicine has, and that is exactly the problem. The mu-opioid receptors that morphine, oxycodone and fentanyl activate are spread through the brain, spinal cord, peripheral nerves and gut, so the relief arrives bundled with constipation, tolerance, dependence and — at the extreme — a shutdown of the brain signals that drive breathing.

A study published October 15 in the journal Cell reports a way to unbundle them. Researchers at Weill Cornell Medicine and the University of Pennsylvania engineered a morphine-derived compound, AM-3, that becomes a potent painkiller only after a brief pulse of light, and only in the tissue the light reaches. In preclinical models that included bone cancer pain and visceral pain, the approach produced morphine-like pain relief with reduced or no signs of tolerance, constipation and other side effects.

A molecule that changes shape on cue

AM-3 is morphine with an azobenzene group attached — a chemical unit that flips between two configurations depending on the wavelength of light it absorbs. Under near-ultraviolet light the molecule settles into a shape that engages the mu-opioid receptor strongly. Under blue light it relaxes into a shape that engages it weakly. The team reported that the switch is reversible and stays stable across many on-and-off cycles, which is what makes a light-controlled drug practical rather than a laboratory curiosity.

The design also keeps most of AM-3 out of the brain. That matters more than it sounds. Respiratory suppression and addiction risk both come from the central side of the receptor's reach, while pain signals can be dampened at the periphery.

"Our goal was to make them safer by controlling them with light in the periphery," said Dirk Trauner, a Penn Integrates Knowledge Professor in Penn's School of Arts & Sciences and Perelman School of Medicine and a co-senior author of the study. "It would be terrible if we would deprive people suffering from debilitating pain from opioids, because they're too important and effective for that."

What the mouse experiments showed

The protocol was deliberately local: inject AM-3, then briefly illuminate the painful site to induce the high-potency shape. In the cancer pain and visceral pain models, that produced analgesia comparable to morphine at the treated site.

The side-effect profile is where the approach diverges from conventional opioid pharmacology. Because the drug is switched on where the light is aimed and cannot easily cross into the brain, the researchers reported reduced or absent tolerance, constipation and other systemic effects in their models.

Structural biology tools, including electron microscopy, guided the design of several candidate molecules before AM-3 emerged as the one that behaved as intended. Vsevolod Katritch and Cornelius Gati at the USC Dornsife College of Letters, Arts and Sciences were major contributors to that work. Luca Posa and Giovanna Romano at Weill Cornell, Xiang Ji at Penn, and Saif Khan and Antonina Nazarova at USC Dornsife are co-first authors.

The ultraviolet problem

AM-3's fast track to the clinic is blocked by its power source. The high-potency shape requires near-ultraviolet light, which can damage eyes and skin. No one is proposing to shine UV light into a patient's knee.

The lab is already working on successors. "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."

Joshua Levitz, a professor of biochemistry and biophysics at Weill Cornell Medicine and the other co-senior author, framed the result as much as a platform advance as a drug advance. "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. Levitz is an inventor on a patent application covering the technology.

The work was supported by the National Institutes of Health, the Rohr Family Research Scholar Award, the Monique Weill-Caulier Award and the Charles H. Revson Fellowship.

Why a safer analgesic matters to the addiction field

AM-3 is not a treatment for opioid use disorder. It is an attempt to keep the condition from starting in the first place, or at least to shrink one of its most common doorways.

Many people who develop opioid use disorder first meet the drugs through a prescription written for surgery, an injury or chronic pain, and prescription pain medications remain among the most frequently misused classes of medication in the United States, according to the Substance Abuse and Mental Health Services Administration. Opioid-involved overdose deaths have fallen for three straight years, but the pipeline that runs from a legitimate prescription to long-term dependence has not been closed, and no one expects a drug that is still being tested in mice to close it soon.

What the Cell paper offers is a different premise for pain medicine: that a drug's site of action can be controlled as precisely as its dose. Anything built on that premise will still have to clear years of toxicology, formulation work and human trials. For people who need strong analgesia and cannot safely be given a conventional opioid, that remains the point.

Treatment with buprenorphine and other medications for opioid use disorder, along with counseling through medication-assisted treatment programs, is the evidence-based path for people who have already developed dependence. Consumer information on how prescription painkiller misuse develops, and where prescription drug abuse treatment is available, is collected in our condition guides.

If you or someone you know is struggling with opioids, the Substance Abuse and Mental Health Services Administration's National Helpline is available around the clock at 1-800-662-4357.