A Descending Pain Modulation Pathway in Green Light-Induced Antinociception

Abstract

In light of the opioid epidemic in the United States, the need for non-opioid treatments of pain is ever-growing. Over the past two decades, phototherapy has been increasingly shown to be efficacious for the treatment of chronic pain. Notably, recent reports have demonstrated green light therapy to be efficacious in the treatment of chronic pain in both pre-clinical and clinical studies. Previous studies in our laboratory have shown that green light therapy requires the visual pathway as well as pain modulating centers in the central nervous system to elicit its antinociceptive effects. However, the specific neural mechanisms engaged within the central nervous system have not yet been fully elucidated. The work in this dissertation sheds light on the involvement of the endogenous opioid system and the descending pain modulatory rostral ventromedial medulla (RVM) in the antinociception induced by green light (GLED) exposure. Chapter 1 elaborates on the various applications and mechanisms of pain phototherapy by way of a literature review, whereas Chapter 2 provides an overview of central pain modulation pathways, particularly that of the descending pain modulatory system. Chapter 3 presents data characterizing the requirement of μ- and d- opioid receptor agonist stimulation by their endogenous agonists, b-endorphin and enkephalin, respectively, in GLED-induced antinociception. Chapter 4 establishes the role of the pain- modulating RVM in GLED-induced antinociception. The results in Chapter 3 prompted an investigation into the role of endogenous opioids in RVM on GLED-induced antinociception, in which it was revealed that opioid-receptor antagonism in the RVM reversed GLED-induced mechanical antinociception, but not thermal antinociception. Selective CRISPR knockout experiments ultimately demonstrated that μ- and d- opioid receptor agonist stimulation in RVM GABAergic neurons is required for GLED-induced mechanical antinociception. To further the translatability of our findings on GLED-induced antinociception to human patients, we conducted a clinical investigation on healthy human subjects to determine the involvement of the ascending and descending pain pathways in GLED-induced antinociception, described in Chapter 4. By using thermal and mechanical assessments of temporal summation and conditioned pain modulation, we determined that GLED-induced antinociception does indeed involve the descending pain pathway. These findings corroborate the results from the animal studies, confirming the contribution of the descending pain pathway in GLED-induced antinociception in both rodents and humans. Finally, in Chapter 5 we report a case study on a colorblind patient in whom GLED exposure therapy was efficacious in decreasing migraine headache pain intensity and improving quality of life and sleep quality measures. The fact that GLED exposure is similarly efficacious in this colorblind patient as is in normal vision patients suggests that the visual pathway through which GLED exposure acts to eventually modulate central pain modulating processes involves a cone-independent, non-image forming mechanism. These findings provide substrate to support the hypothesis that intrinsically photosensitive retinal ganglion cells may be responsible for the route of entry for GLED exposure that eventually results in pain neuromodulation