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Green Light May Reduce Chronic Pain Via the Brain’s Opioid System

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A new study has unraveled the neural circuits that explain how green light can relieve some cases of chronic pain. The neurons ultimately activate the brain’s own opioid system.

To many people living with chronic pain, routine pharmacological treatments provide no relief from their discomfort or have devastating side effects. To address these intractable conditions, clinicians have tried approaches that stray far from the standard drug-based model of pain relief. For some, these interventions can provide long-awaited benefits from their pain. One of these approaches is light therapy (phototherapy), where patients are exposed to light of certain wavelengths and intensities to try and relieve pain.

This approach remains experimental but has been deployed, with some success, to reduce pain in conditions like lower back pain, fibromyalgia, migraine and neuropathic pain. Of the wavelengths used, green light has most commonly appeared to have a beneficial effect.

While the focus for patients is undoubtedly on whether these treatments work, for researchers the why of phototherapy has proved intriguing. A new paper has used mouse models of pain to dig into the neural mechanisms behind light-based pain relief, suggesting that activation of the brain’s natural opioid receptors may play a role.

Light and medicine

Pain relief is just one application of light in medicine, or phototherapy. Previous studies have investigated phototherapy for the inflammatory skin disease psoriasis, sleep and affective disorders and even, in combination therapies, for nanomedicine in cancer treatment.

The research, published in Science Translational Medicine, was authored by a Chinese research team led by Fudan University’s Prof. Yu-Qiu Zhang.

Shining a light on chronic pain

The effect of light on pain reduction has been well-established in pre-clinical models, so the researchers’ first step was to confirm these earlier findings by showing that green light exposure in mice with a form of arthritis reduced pain. They then explored how this effect was altered in mice that lacked various structures in their eyes that detected visual input.

The mammalian eye receives input through three types of receptors – each of which respond to different wavelengths of light: rods and cones in the outer retina, and a third class of receptor called melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGC) in the inner retina. The researchers showed that when rods and cones were absent, the mice received no benefit from the green light stimulation. When only cones were absent, the effect was also completely abolished, but mice with no rod receptors still had a mild reduction in pain. When ipRGCs were removed, the mice showed no reduction in pain. This suggested to the researchers that the neural pathway they were unraveling began with rod and cone photoreceptors.

Tracing a neural pain pathway

Rods and cones feed the information they receive about the outside world onto retinal ganglion cells (RGCs) that convey these signals to higher brain areas. Zhang and team followed this biological thread, using genetic or pharmacological silencing of particular neuronal populations at each stage. They found that connections between the RGCs and the ventral lateral geniculate nucleus (vLGN), a part of the thalamus (the brain’s sensory switchboard) that processes visual information, mediated the analgesic effect.

The vLGN is filled with neurons that send inhibitory signals using the neurotransmitter GABA. The team noted that 32% of the GABAergic neurons in the vLGN also expressed the Penk gene, which codes for a protein, PENK.

This is a precursor to another molecule, ENK, which activates opioid receptors in the brain. The PENK-producing neurons communicated with a region of the brain called the dorsal raphe nucleus (DRN) found in the brainstem. The DRN is thought to have an important role in pain control. When the researchers genetically altered their mice so that their brains couldn’t send PENK to the DRN, the pain-reducing effect of green light disappeared: the team had found the end of their path.

Looking into the light

But it isn’t the end for the research field. Experiments utilizing genetic knockout animals to explore the contribution of various brain circuitry to observed behavior are now a staple of neuroscience. The paper’s authors acknowledge that other structures in the cortex might also play a role in the effects of light therapy, and more circuity-untangling studies will be required to separate these different strands.

Another pressing question is why exactly green light would have an analgesic effect in the first place. What could the evolutionary benefit of such a mechanism be? The authors point in their discussion towards a disparate research body that draws from neuroscience and psychology.

“Exposure to an environment rich in the color green (such as [the Japanese and Chinese practice] forest bathing) can decrease physiological and psychological pain. Psychology studies have shown that “green” conveys positive information related to happiness,” the authors write.

The authors also point to research suggesting that other forms of sensory input can mitigate pain: a 2019 paper showed than when humans were exposed to painful stimuli, those who were simultaneously given a sweet smell or taste stimulation rated the pain lower than those given a bitter input.

There are complex interplays involved between our many senses, including pain detection, and the authors finally conclude that the ultimate reason for their findings “might be explained by functional connectivity among primary somatosensory, visual, auditory cortex, and other cortical areas (such as prefrontal cortex) that participate in cross-modal processing.”

Reference: Tang Y, Liu A, Lv S et al. Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus. Sci. Trans. Med. 2022; 14: eabq6474. doi: 10.1126/scitranslmed.abq6474