A morphine-based compound activated by light relieved pain in preclinical models while showing fewer signs of several common opioid side effects, researchers led by Weill Cornell Medicine and the University of Pennsylvania report. The experimental drug has not been tested in people, and its use of ultraviolet light remains a barrier to clinical development.
The compound, called AM-3, changes shape when exposed to different wavelengths, changing how strongly it activates the mu-opioid receptor, according to a Cornell Chronicle account of the study. The research was published Oct. 15 in Cell. It offers a way to concentrate an opioid's effect at a pain site rather than expose the whole body to the same activity.
Pain relief where light was applied
The researchers engineered several morphine-based compounds joined to azobenzene structures, which can change shape in response to light and switch back again. They used electron microscopy and other structural tools to examine how the compounds interacted with the receptor targeted by opioid medicines. AM-3 emerged as a candidate that activated that receptor strongly after near-ultraviolet exposure and more weakly after blue-light exposure.
In preclinical models of bone-cancer and visceral pain, the team injected AM-3 and briefly illuminated the pain site with near-ultraviolet light. The treatment produced a morphine-like pain-relieving effect in the illuminated area, Cornell reported. The tests showed reduced or no signs of tolerance, constipation and other side effects measured in those models.
AM-3 also crosses into the brain poorly, which the researchers say may help limit effects tied to brain exposure, including addiction and suppression of breathing. But animal and other preclinical results cannot establish that the compound would avoid those risks in people. Human safety, dosing, effectiveness and a practical way to deliver light to deeper tissues remain unresolved.
Mu-opioid receptors occur in the brain, spinal cord, peripheral nerves and gut. Existing opioids can provide powerful pain relief, but their activity throughout the body can cause constipation and tolerance; brain effects can contribute to dependence and dangerous breathing suppression. The AM-3 approach aims to separate useful pain relief from some of those unwanted effects by controlling when and where the drug is potent.
More development needed before human use
The light requirement presents a major limitation. Near-ultraviolet light can damage skin and eyes, and it does not penetrate tissue as deeply as longer wavelengths. The team is working on successor compounds that could respond to visible light, potentially including red light, before considering clinical trials.
Joshua Levitz, a Weill Cornell Medicine professor and study co-senior author, said the results may also advance the broader technique of photopharmacology, which uses light to control drug activity. The work was conducted with the laboratory of University of Pennsylvania professor Dirk Trauner. Researchers at the University of Southern California also contributed structural and computational work.
Study co-first authors include Luca Posa and Giovanna Romano of Weill Cornell Medicine, Xiang Ji of the University of Pennsylvania, and Saif Khan and Antonina Nazarova of USC. Levitz is listed as an inventor on a patent application related to the technology. Funding came from the National Institutes of Health and several research awards and fellowships.
The investigators hope to move through further preclinical development before any human testing; the current findings are a laboratory advance, not an available or proven safer pain medicine.
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