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Exposure to green light promises to help treat chronic pain, offering ease of use and negligible side effects.

Credit: Kris Hanning/University of Arizona Health Sciences

Yehia Mechref will discuss how to leverage proteomics and glycoproteomics tools to identify predictive biomarkers of neurodegenerative diseases and traumatic brain injury.

Topics to be covered

Using glycoproteins as effective predictors of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases
Detecting glycoproteins predictors of traumatic brain injury

Thursday, March 21st, 2024 | 1:00 PM – 2:00 PM Eastern Time
This webinar will be available to view live and on demand.

Speaker

Yehia Mechref, PhD

Director, Center for Biotechnology and Genomics
Texas Tech University

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Scientists once believed that the central nervous system was inaccessible to antibody therapeutics. With emerging evidence that antibodies cross the blood-brain barrier, researchers are now developing innovative treatments.

Download this poster from Drug Discovery News to learn about recent advances in antibody therapeutics for treating neurological diseases.

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Download this poster from Drug Discovery News to learn about recent advances in antibody therapeutics for treating neurological diseases.

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Small interfering RNAs (siRNAs) are a new class of oligonucleotide therapeutics that degrade disease-causing mRNA. However, restrictions imposed by the blood-brain barrier and short circulation times limit the therapeutic potential of siRNAs for brain disorders. In this webinar, Julia Alterman will discuss an innovative approach to achieve potent and long-term siRNA activity in the brain using a novel chemical scaffold that enables widespread siRNA brain delivery and gene silencing.

Topics to be covered

A novel siRNA chemical scaffold for widespread brain delivery
Potent and long-term gene silencing in the mouse and nonhuman primate brain

Wednesday, October 11th, 2023 | 2:00 PM – 3:00 PM Eastern Time
This webinar will be available to view live and on demand.

Speaker

$\"Julia$

Julia Alterman, PhD

Assistant Professor
University of Massachusetts Chan Medical School

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Topics to be covered

A novel siRNA chemical scaffold for widespread brain delivery
Potent and long-term gene silencing in the mouse and nonhuman primate brain

Wednesday, October 11th, 2023 | 2:00 PM – 3:00 PM Eastern Time
This webinar will be available to view live and on demand.

Speaker

Julia Alterman, PhD

Assistant Professor
University of Massachusetts Chan Medical School

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increasingly demonstrate the soothing effects of green light, and now, researchers are revealing the underlying neural mechanisms.”},{“property”:”og:image”,”content”:” Discovery News”},{“property”:”og:url”},{“name”:”twitter:card”,”content”:”summary_large_image”},{“name”:”twitter:title”,”content”:”Lighting the way to pain relief”},{“name”:”twitter:description”,”content”:”Rodent studies and clinical trials increasingly demonstrate the soothing effects of green light, and now, researchers are revealing the underlying neural mechanisms.”},{“name”:”twitter:image”,”content”:”

Every now and then, Mohab Ibrahim’s brother gets headaches. For years, Ibrahim, an anesthesiologist and pharmacologist at the University of Arizona, advised him to take medication like ibuprofen, but his brother would respond that he preferred sitting in his garden for relief. Ibrahim never gave much thought to his brother’s peculiar remedy, until one day he himself had a headache and no medication at home. On his way to the pharmacy, he stopped by a park in Tucson and stayed there for about 30 minutes. His headache subsided.

Mohab Ibrahim and Laurent Martin point out a graphical representation of a neuron on a computer in a laboratory.

University of Arizona pharmacologist Mohab Ibrahim (left) and neuroscientist Laurent Martin (right) are exploring the neural mechanisms behind the pain-relieving effects of green light.

Credit: Kris Hanning/University of Arizona Health Sciences

“I went back to my office, and for the first time, actually, I started thinking about what my brother was saying,” Ibrahim recalled. Because of his pharmacology background, he first considered if trees could be releasing some kind of chemicals into the air. However, after further thought, he considered whether the color green, common to all gardens and parks, might be involved in these pain-relieving effects. Although he found no research exploring that specific link at the time, studies showing that bright light therapy helped mood disorders gave him the first clue about light’s potential biological effects (1).

Motivated to find out whether specific colors could affect pain, he and his colleagues exposed rats to light-emitting diodes (LEDs) of different colors and observed their behavior. “We turned our lab into a disco ground,” he said. They found that when exposed to two colors of light — green and blue — the rats became less sensitive to painful heat stimuli (2). The team decided to focus only on green, since blue light suppresses melatonin secretion and can disturb sleep if used incorrectly (3).

These early observations set the stage for a growing collection of evidence for the pain-relieving effects of green light. Ibrahim’s team and others have now even tested green light in small human cohorts and are also gradually uncovering the underlying mechanisms of its effects (4). Although it likely won’t be a silver bullet to end pain, experts agreed that its ease of use and absence of reported side effects are encouraging for helping patients with chronic pain.

**Could green be the new pill?**

While certainly intriguing, the notion that a group of rats experienced pain differently due to green light exposure took many years to gain credibility. “There was a lot of skepticism when we started publishing, but now a lot of teams have reproduced the results all around the world,” said Laurent Martin, a neuroscientist at the University of Arizona who collaborates with Ibrahim. Following Ibrahim’s initial experiment in rats, subsequent studies showed that exposure to green LEDs (GLEDs) reduced pain-like behavior in osteoarthritis rat models and attenuated the animals’ hypersensitivity after undergoing surgery (5-7). According to various studies, mice also benefit from the analgesic-like effects of green light (8-10).

Martin recalled that when he moved to Arizona in 2019 to start studying green light therapy, the idea was then just a proof of concept. “We knew that green light could reduce pain in animal models. It was just the beginning, and we knew nothing [else] about it.” He and his colleagues were eager to understand the underlying mechanisms as well as to translate it to humans.

Mohab Ibrahim and Laurent Martin point to a device that measures light intensity inside a laboratory illuminated with green light-emitting diodes.

Researchers at the University of Arizona investigate the optimal intensity of green light-emitting diodes for treating chronic pain.

Credit: Kris Hanning/University of Arizona Health Sciences

Because LED-based therapy is very safe, testing the analgesic effects of green light in humans was one of the team’s first focuses. “It’s not laser, so it’s not going to hurt the eyes; it doesn’t have UV [light], so it’s not going to cause cancer or anything like that,” Ibrahim said. Given the prevalence and difficulty of managing migraine and fibromyalgia, they started two clinical trials focusing on green light for these conditions.

The team asked patients in both trials to sit in front of an LED strip in a dark room at home for one to two hours daily. For ten weeks, the LED strip emitted white light, followed by a two-week treatment break, and then it shined green light for ten weeks. Exposure to green light significantly reduced the number of days where patients reported pain — from an average of 7.9 to 2.4 in those with episodic migraines and from 22.3 to 9.4 in those with chronic migraines (11). White light exposure also reduced headache days but to a much lesser extent. Green light also reduced the intensity and duration of headache attacks. Patients with fibromyalgia following the same protocol reported a nearly 60 percent reduction in pain intensity on a numeric scale (4). White LED exposure did not reduce pain scores in the fibromyalgia trial. None of the participants in the trials reported any side effects.

Another independent pilot study on fibromyalgia hinted at green light having some analgesic effects (12). Instead of sitting in a room with GLEDs, patients used either clear glasses, blue-, or green-light filtering glasses for at least four hours per day for two weeks. “I was looking for a thing that people can adapt easily … that they can go about their daily business,” said Padma Gulur, a pain researcher at Duke University who led the trial. The team reported that patients wearing green glasses reduced, albeit not significantly, their daily opioid requirements to treat the chronic disease. Pain scores were not significantly different between those wearing clear and green glasses.

Harvard Medical School’s pain scientist Rami Burstein and his team studying migraine-related photophobia — feeling pain or discomfort due to light exposure — reported that green light exacerbated headache pain less than white, blue, amber, and red lights in patients with migraine (13). Furthermore, their study showed that green light reduced pain intensity in 20 percent of the 69 participants. In a larger open-label trial with 181 individuals, two hours of exposure to a green light lamp during migraine attacks improved the patients’ headache perception in 55 percent of all reported events (14).

“Do we know green light absolutely helps pain? I can’t say that,” Gulur acknowledged. “There’s a very good signal that we are able to affect perception of pain with green light,” she added, but “we need to do much larger-scale randomized control trials.”

A journey from the eye to the brain

Ibrahim, who cofounded the startup company Luxxon Therapeutics, to commercialize this therapy, said that the positive impact of green light in patients, the absence of any side effects so far, and the affordability of the therapy got his team really excited. “That made us start focusing on the mechanisms. How was this happening?” he asked. “Because once we have an understanding of the mechanism, then we can make it better or find other indications for it.”

For one, all of the evidence so far supports that green light acts on pain through the visual system and not through the skin. Ibrahim and his team saw this firsthand when they found that rats wearing opaque contact lenses did not respond to the green light therapy (2). The specific involvement of each of the three types of photoreceptor cells in the eyes — cones, rods, and intrinsically photosensitive retinal ganglion cells (ipRGCs) — is debatable.

While cones and rods help define the form of all the things humans see, ipRGCs are nonimage-forming cells due to the poor spatiotemporal resolution and contrast sensitivity of melanopsin, the light-sensitive protein they contain. Yet, melanopsin detects changes in ambient light intensity, playing a key role in regulating the internal mammalian clock. Blind individuals with migraines who have intact ipRGCs but severely damaged rods and cones still suffer from photophobia, which suggested the involvement of these cells in exacerbation of headache pain by light (15). Furthermore, the team found that ipRGCs project into the posterior thalamus in rats, a brain region involved in processing pain, supporting the involvement of these nonimage-forming cells in the relationship between light and pain (15). A study led by Burstein also reported the involvement of cones, which are responsible for detecting color, in migraine photophobia (13).

There’s a very good signal that we are able to affect perception of pain with green light.
– Padma Gulur, Duke University

A couple of years ago, though, a study in mice led by Fudan University neuroscientist Yu-Qiu Zhang reported no involvement of ipRGCs in green light’s analgesic effects (9). Using a chemical that destroyed more than 80 percent of the ipRGC population in the eyes of arthritic mice, the team observed no change in the animals’ pain response to green light. In contrast, mice without functional rods showed a partial reduction in green-light mediated pain relief, while those with destroyed cones experienced no pain relief at all.

“We were puzzled by these results,” said Martin. However, he noted that the study was done in mice, which could partially explain the discrepancy between these results and the hypothesis that ipRGCs linked light and pain, based on reports of photophobia in blind humans (15). So far, no further evidence has ruled out the role of ipRGCs in these pain-relieving effects. Martin, who also works at Luxxon Therapeutics, said he is interested in reproducing these studies to confirm that these photoreceptors are indeed not involved.

There is, however, greater consensus on the neural pathways at play. Zhang and colleagues found that a subset of neurons in the ventrolateral geniculate nucleus (vLGN) in the thalamus are key to green light’s pain-relieving effects (9). These neurons express proenkephalin, which is the precursor of enkephalin, an endogenous opioid involved in pain modulation. Ibrahim’s team also found an increased expression of enkephalins in the spinal cords of rats exposed to GLEDs (2).

Based on animal studies so far, researchers think that green light primarily activates the cones, potentially the rods, and with less certainty, the ipRGCs. This signal results in retinal projections that reach the vLGN, activating enkephalinergic neurons, which in turn project to pain modulating brain areas. This increases the release of enkephalins and other endogenous opioids leading to pain relief.

“The brain is a very intricate network,” Martin said. There are likely other pathways involved, he added. For instance, experiments in rodents also suggested the involvement of the periaqueductal gray, a pain modulation brain structure, and the glutamatergic system in the healing power of green (2,10).

Gulur hypothesized that the amygdala, which plays a role in the emotional responses to pain, could be another player in these complex interactions. Although there is no evidence yet, both Gulur and Martin are interested in exploring its potential involvement. Since green light has also reduced anxiety in patients, “I wouldn’t be surprised that green light modulates the amygdala activity,” said Martin (14).

Gulur, who has a patent pending for green light-based analgesia, said that equally important to unraveling the mechanisms involved in it is improving the understanding of the most effective therapy’s parameters, such as optimal doses and wavelengths, and identifying other pain conditions it may help. “Whether we understand the mechanism or not, I’m less worried because there’s so much we don’t fully understand,” she said. “Once you start seeing this benefit, it behooves us to advance the science.”

References

Pail, G. et al. Bright-Light Therapy in the Treatment of Mood Disorders. Neuropsychobiology 64, 152-162 (2011).

Ibrahim, M. et al. Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain 158, 347-360 (2017).

Wahl, S. et al. The inner clock—Blue light sets the human rhythm. J Biophotonics 12, e201900102 (2019).

Martin, L. et al. Green Light Exposure Improves Pain and Quality of Life in Fibromyalgia Patients: A Preliminary One-Way Crossover Clinical Trial. Pain Med 22, 118-130 (2021).

Ventura, L. et al. Effects of Green Light Therapy on Pain-like Behavior and Inflammatory Markers in an Osteoarthritis Model in Rats. The Journal of Pain 25, 66 (2024).

O’Brien, M.S. et al. Green Light Therapy Reduces Mechanical Pain In A Rat Model Of Osteoarthritis By Activating The Endocannabinoid System. Osteoarthritis and Cartilage 31, S377 (2023).

Martin, L.F. et al. Green Light Exposure Elicits Anti-inflammation, Endogenous Opioid Release and Dampens Synaptic Potentiation to Relieve Post-surgical Pain. J Pain 24, 509-529 (2023).

Cao, P. et al. Green light induces antinociception via visual-somatosensory circuits. Cell Rep 42, 112290 (2023).

Tang, Y.-L. et al. Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus. Sci Transl Med 14, eabq6474 (2022).

Wu, X.-Q. et al. Glutamatergic and GABAergic neurons in the vLGN mediate the nociceptive effects of green and red light on neuropathic pain. Neurobiol Dis 183, 106164 (2023).

Martin, L.F. et al. Evaluation of green light exposure on headache frequency and quality of life in migraine patients: A preliminary one-way cross-over clinical trial. Cephalalgia 41, 135-147 (2021).

Gulur, P. et al. Green Light-Based Analgesia – Novel Nonpharmacological Approach to Fibromyalgia Pain: A Pilot Study. Pain Physician 26, 403-410 (2023).

Noseda, R. et al. Migraine photophobia originating in cone-driven retinal pathways. Brain 139, 1971-1986 (2016).

Lipton, R.B. et al. Narrow band green light effects on headache, photophobia, sleep, and anxiety among migraine patients: an open-label study conducted online using daily headache diary. Front Neurol 14, 1282236 (2023).

Noseda, R. et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci 13, 239-45 (2010).

Mohab Ibrahim’s brother gets headaches. For years, Ibrahim, an anesthesiologist and pharmacologist at the University of Arizona, advised him to take medication like ibuprofen, but his brother would respond that he preferred sitting in his garden for relief. Ibrahim never gave much thought to his brother’s peculiar remedy, until one day he himself had a headache and no medication at home. On his way to the pharmacy, he stopped by a park in Tucson and stayed there for about 30 minutes. His headache subsided.

University of Arizona pharmacologist Mohab Ibrahim (left) and neuroscientist Laurent Martin (right) are exploring the neural mechanisms behind the pain-relieving effects of green light.

Credit: Kris Hanning/University of Arizona Health Sciences

**Could green be the new pill?**

Researchers at the University of Arizona investigate the optimal intensity of green light-emitting diodes for treating chronic pain.

Credit: Kris Hanning/University of Arizona Health Sciences

A journey from the eye to the brain

There’s a very good signal that we are able to affect perception of pain with green light.
– Padma Gulur, Duke University

References

Pail, G. et al. Bright-Light Therapy in the Treatment of Mood Disorders. Neuropsychobiology 64, 152-162 (2011).

Ibrahim, M. et al. Long-lasting antinociceptive effects of green light in acute and chronic pain in rats. Pain 158, 347-360 (2017).

Wahl, S. et al. The inner clock—Blue light sets the human rhythm. J Biophotonics 12, e201900102 (2019).

Martin, L. et al. Green Light Exposure Improves Pain and Quality of Life in Fibromyalgia Patients: A Preliminary One-Way Crossover Clinical Trial. Pain Med 22, 118-130 (2021).

Ventura, L. et al. Effects of Green Light Therapy on Pain-like Behavior and Inflammatory Markers in an Osteoarthritis Model in Rats. The Journal of Pain 25, 66 (2024).

O’Brien, M.S. et al. Green Light Therapy Reduces Mechanical Pain In A Rat Model Of Osteoarthritis By Activating The Endocannabinoid System. Osteoarthritis and Cartilage 31, S377 (2023).

Martin, L.F. et al. Green Light Exposure Elicits Anti-inflammation, Endogenous Opioid Release and Dampens Synaptic Potentiation to Relieve Post-surgical Pain. J Pain 24, 509-529 (2023).

Cao, P. et al. Green light induces antinociception via visual-somatosensory circuits. Cell Rep 42, 112290 (2023).

Tang, Y.-L. et al. Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus. Sci Transl Med 14, eabq6474 (2022).

Wu, X.-Q. et al. Glutamatergic and GABAergic neurons in the vLGN mediate the nociceptive effects of green and red light on neuropathic pain. Neurobiol Dis 183, 106164 (2023).

Gulur, P. et al. Green Light-Based Analgesia – Novel Nonpharmacological Approach to Fibromyalgia Pain: A Pilot Study. Pain Physician 26, 403-410 (2023).

Noseda, R. et al. Migraine photophobia originating in cone-driven retinal pathways. Brain 139, 1971-1986 (2016).

Noseda, R. et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci 13, 239-45 (2010).

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University of Arizona pharmacologist Mohab Ibrahim (left) and neuroscientist Laurent Martin (right) are exploring the neural mechanisms behind the pain-relieving effects of green light.