This application addresses the critical need for efficacious non-pharmacological treatments for humanimmunodeficiency virus type 1 (HIV) sensory neuropathy (HIV-SN). This neuropathy can be associated withviral infection alone likely involving a role for the envelope glycoprotein gp120; or a drug-induced toxicneuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) as acomponent of highly active anti-retroviral therapy. Dr. Mohab Ibrahim Principal Investigator on this projectalong with Dr. Rajesh Khanna a co-Investigator on this project first showed that low intensity green lightprovided long-lasting antinociception in nave animals. No side-effects were noted and motor performance wasnot impaired. The antinociception may be due to increased endogenous opioid expression observed in thespinal cord and possibly the decrease in inflammatory factors. Their recent work also demonstrated reversal ofmechanical and thermal hypersensitivity in rats subjected to spinal nerve ligation a model of chronicneuropathic pain. Thus understanding the mechanisms that contribute to green light mediated antinociceptionwould be a critical first step in developing this as a novel form of therapy. We will test our hypothesis thatexposure to green light will reduce thermal mechanical hypersensitivity due to engagement of theendogenous opioid system and decrease inflammatory mediators. We will test this hypothesis with fourrelated but independent specific aims using the envelope glycoprotein gp120 model of HIV-induced painfulperipheral neuropathy. We will first determine the time-course and light intensity (lux levels) needed forreversal of thermal and mechanical hypersensitivity in the gp120 model of HIV-induced painful peripheralneuropathy and the mechanical hypersensitivity associated with antiretroviral therapy (SA1). Next we willdetermine the contribution of the endogenous opioid system in mediating the effects of green light emittingdiode (GLED) and whether a fixed light intensity/duration along with a mu opioid receptor agonist or a nonopioid neuropathic pain medication such as gabapentin result in a synergistic antinociceptive effect in animalswith gp120-induced neuropathy (SA2). We will characterize cellular activation and determine the levels ofinflammatory cytokines in the spinal cord dorsal horn brain cerebrospinal fluid and plasma from rats withgp120-induced neuropathy and following GLED exposure (SA3). Finally we will investigate possible sideeffects that may be associated with prolonged exposure to green light therapy in preparation for introducingthis therapy to human patients (SA4). Green light therapy resulting in decreased chronic pain without sideeffects has the promise of being easily translatable into the clinic due to their apparent efficacy safety low costand availability. Our studies may offer an adjunct to current clinical therapies likely resulting in reducingopioids to manage HIV induced neuropathic pain as well as other chronic pain states. Importantlywith a reduction in their pain HIV patients may be more compliant with their antiretroviral therapy.