Chronic musculoskeletal pain (cMSP), including fibromyalgia, affects over 14% of the population, is a leading cause of disability worldwide, and is often refractory to available treatments. New, non-addictive treatment options are urgently needed to improve the management of cMSP and reduce reliance on opioids. Light therapy delivered to the retina promises to be a powerful, non-pharmacologic therapy to ameliorate cMSP. Evidence is mounting for the analgesic effect of light in common cMSP conditions (e.g., fibromyalgia, chronic low back pain). Despite the incredible promise, the neural mechanisms and properties of light that drive analgesia remain poorly understood. Elucidating these details of the underlying neural mechanisms will unlock the full potential of light therapy for treating cMSP. These details include discovering how activation of specific visual system circuitry modulates pain, including identifying the neurons in the retina involved and tracing out the distribution of their signals in the brain and their interactions with pain pathways. We hypothesize that light-driven analgesia operates through specific visual pathways originating at the level of color-sensitive ganglion cells in the retina. Color-sensitive ganglion cells receive excitatory and/or inhibitory input from short (S-), middle (M-), and long (L-) wavelength-sensitive cone photoreceptors (e.g. S vs L/M). Green light has been recently implicated as a color of light that drives analgesic pathways far greater than white light of equal brightness, a hallmark of a color-sensitive retinal mechanism. This proposal brings together an integrated team with demonstrated expertise in vision neuroscience, optoelectrical engineering, neuroimaging, and translational pain research to comprehensively evaluate the retinal, subcortical, and cortical color-opponent mechanisms involved in light-driven analgesia. The specific aims will be done in parallel using homologous model systems that translate to humans. In this proposal, we will (1) Identify color-sensitive retinal ganglion cells that mediate analgesia and characterize their light responses using extracellular and whole-cell voltage-clamp recordings in the primate and rat retina to determine the optimal stimulus paradigms (spatial/temporal frequency, wavelength) to drive analgesic circuits, (2) Evaluate the cortical and subcortical responses to retinal stimuli that drive these color-sensitive ganglion cells to elucidate the brain mechanisms of light-driven analgesia in humans with cMSP, and (3) Map the analgesic circuit that carries signals from color-sensitive ganglion cells to the rat central nervous system and behaviorally link circuits activated by colored-light to pain circuits by trapping circuits driven by color-sensitive ganglion cells in a validated rat model of cMSP. Together, these aims will provide critical mechanistic insights into the interplay between retinal and pain circuits that carry chromatic information and will a...