Study Traces a Neural Circuit Behind Green Light-Mediated Pain Relief

In recent years, studies in rodents and humans have suggested that exposure to light may reduce chronic pain. Green light, in particular, has been reported to relieve pain in people with migraines and fibromyalgia. However, little is known about the mechanism behind these observations. A study published yesterday (December 7) in Science Translational Medicine unravels part of this mystery: The researchers conclude that in mice, this green light analgesia is mediated mainly by cones, the photoreceptor cells in the eye responsible for detecting color and, to a lesser extent, by rods, another photoreceptor in the eye. They also pinpoint a subset of neurons in a thalamic structure involved in this effect.

This study is important because it confirms observations of green light-mediated analgesia that were previously made by other, independent groups—“something that only very few groups in the world . . . have looked at,” says University of Arizona anesthesiologist and pharmacologist Mohab Ibrahim, who did not participate in this work but who studies the green light effects at the University of Arizona. Figuring out “what really changes in the brain” when someone is exposed to green light is also valuable, he adds, as it may help researchers develop new treatments for various conditions. Ibrahim is a coinventor of a patent for using green light therapy to manage chronic pain and is one of the founders of Luxxon Therapeutics, LLC, a startup company interested in commercializing this therapy.

The team of researchers behind the new study, who are based at Fudan University in Shanghai, exposed arthritic mice to low-intensity green light for eight hours per day for six days and measured their thermal and mechanical hypersensitivity—that is, whether they would remove their paw from an unpleasant heat or tactile stimulus—before, during, and after this treatment period. In accordance with previous works, the team’s findings revealed that green light significantly reduced pain sensitivity in these mice.

Then, the authors investigated which photoreceptors were mediating this effect. To this end, they genetically or pharmacologically inhibited each of the three types present in the mammalian retina: cones, rods, and intrinsically photosensitive retinal ganglion cells (ipRGCs)—the latter of which are associated with nonvisual responses to light. Even when the researchers reduced the density of ipRGCs by more than 80 percent using a chemical that destroys some but not all these cell subtypes, they didn’t measure any change in the light’s analgesic effect. However, transgenic mice lacking rod function showed a partial reduction in pain relief. The change was even more dramatic in mice where cones were ablated using a toxin transgene: In this condition, the analgesic effect of green light exposure vanished altogether.

The team next attempted to trace the neural circuitry that transmitted the photoreceptors’ signals and ultimately resulted in an analgesic effect. A series of experiments where neural populations were either inhibited or activated revealed that a subset of neurons that express the protein proenkephalin (PENK) was key for green light analgesia. PENK is a precursor of the peptide enkephalin, which relieves pain by binding to two types of opioid receptors. These neurons are located in the ventrolateral geniculate nucleus (vLGN) of the thalamus, a brain region that’s responsible for relaying sensory signals, and were already known to receive input from the retina. Earlier studies determined that these neurons’ axons project to the dorsal raphe nucleus (DRN), a structure in the brainstem associated with pain modulation. When the team selectively inhibited these vLGN^Penk neurons’ projections into the DRN, they found that the effects of green light in mice disappeared.

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Taken together, these experiments led the authors to conclude that green light analgesia results from light reception, primarily via cones, which communicate the signal to PENK-expressing neurons in the vLGN that project into the DRN in the brainstem.

The most exciting finding of this paper is the identification of “a pathway to which light could engage a pain modulating system,” says Oregon Health and Science University neuroscientist Mary Heinricher, who did not participate in this study. “By actually looking at the thalamic structure that directly receives this retinal input and then very directly connects with the pain modulating system,” the authors can unravel one of the pathways involved in the analgesic effect of green light. Yet, she adds, this might be only one of “multiple pathways.”

Padma Gulur, a pain researcher at the Duke University School of Medicine who did not participate in this work but has a patent pending for green light-based analgesia, says that these findings offer evidence for one potential mechanism of how green light-mediated analgesia works, but that the identification of this pathway does not discard other potential photoreceptors and circuits involved. These results do “not fully explain what we’re seeing” in clinical studies, she adds. For instance, light has been shown to have an analgesic effect in a colorblind patient—a finding that’s hard to explain with the new study, since colorblindness stems from nonfunctioning cones. Based on these observations and the fact that some ipRGCs remained intact when they were inhibited in the new study’s experiments, Gulur says the role of these cells cannot be entirely excluded—a caveat acknowledged by the authors in their paper.

Improving our understanding of how this green light-mediated analgesic effect works may inform how to “set up protocols” for light therapy that could effectively treat pain, says Heinricher. In the end, light therapy promises to be “a cheap, easy treatment,” she adds, arguing that the accumulating evidence of its potential benefits ought to inspire researchers to “test it as actively as we can.”