Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review

Abstract

A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is being increasingly utilized for the management of a variety of pain conditions. The modes of delivery, and hence applications of phototherapy, vary by wavelength, intensity, and route of exposure. As such, differing mechanisms of action exist depending upon those parameters. Cutaneous application of red light (660 nm) has been shown to reduce pain in neuropathies and complex regional pain syndrome-I, whereas visual application of the same wavelength of red light has been reported to exacerbate migraine headache in patients and lead to the development of functional pain in animal models. Interestingly visual exposure to green light can result in reduction in pain in variety of pain conditions such as migraine and fibromyalgia. Cutaneous application typically requires exposure on the order of minutes, whereas visual application requires exposure on the order of hours. Both routes of exposure elicit changes centrally in the brainstem and spinal cord, and peripherally in the dorsal root ganglia and nociceptors. The mechanisms of photobiomodulation of pain presented in this review provide a foundation in furtherance of exploration of the utility of phototherapy as a tool in the management of pain. PERSPECTIVE: This review synopsizes the pathways and mechanisms through which light modulates pain and the therapeutic utility of different colors and exposure modalities of light on pain. Recent advances in photobiomodulation provide a foundation for understanding this novel treatment for pain on which future translational and clinical studies can build upon.

Keywords: Pain management; complementary medicine; light therapy; photoreception; visual exposure.

Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Neural pathways of visual phototransduction leading to pain induction or exacerbation.

Exposures to light have been reported to induce or exacerbate pain by eliciting changes in pain processing and modulating centers in the brain and brainstem. The importance of the olivary pretectal nucleus in these pathways has been corroborated by multiple studies. The pain-modulating rostral ventromedial medulla can be switched to a pronociceptive state following light exposure. In the setting of migraine, light input and meningeal nociception signals ultimately converge on the thalamus to project to cortical areas of pain processing, resulting in photophobia. Abbreviations: ipRGC, intrinsically photosensitive retinal ganglion cells; OPN, olivary pretectal nucleus; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; SSN, superior salivatory nucleus.

Figure 2.. Mechanisms of visual phototransduction leading to analgesia.

Visual applications of light elicit central changes such as increased enkephalin mRNA expression and decreased calcium influx. Applications of bright light have been shown to modulate circadian rhythms that also contribute to an overall analgesic effect. Abbreviations: CaV2.2, N-type voltage-gated calcium channel; ipRGC, intrinsically photosensitive retinal ganglion cells; OPN, olivary pretectal nucleus; PAG, periaqueductal gray; PENK, proenkephalin-A; RVM, rostral ventromedial medulla.

Figure 3.. Mechanisms of cutaneous phototransduction leading to analgesia.

Application of light cutaneously has peripheral and central effects to reduce pain. Peripheral mechanisms include modulation by pro- and anti-inflammatory cytokines, immune cell recruitment and activation, and decreased expression of receptors involved in neuronal transmission. Central mechanisms involve reduction of inflammatory cytokines and receptors responsible for pain transmission. Abbreviations: DRG, dorsal root ganglion; HIF-1α, hypoxia-inducible factor-1α; IL-1β, interleukin 1β; IL-10, interleukin 10; IR, infrared; mGLuR1, metabotropic glutamate receptor type 1; NIR, near-infrared; PAP, prostatic acid phosphatase; TBARS, thiobarbituric acid reactive species; TNF-α, tumor necrosis factor α; TRPV1, Transient Receptor Potential Vanilloid 1.