Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of widely used antitumoral agents in the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) & proteasome-inhibitor (e.g., bortezomib) classes.1-3 Thus, CIPN is one of most common causes of dose reduction & discontinuation of what is otherwise a life-saving therapy.2-7 Addressing this major public health issue by identifying therapeutic targets with immediate potential translation to the clinic is of paramount significance. We have identified A3 adenosine receptor (A3AR) agonism as a new viable therapeutic strategy for treating or reversing CIPN (Appendix 1 & ref8). Noteworthy, the selective A3AR agonists IB-MECA & its 2-chloro analogue (Cl-IBMECA) are in advanced clinical trials as anti inflammatory and antitumor agents.9,10 This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore the breadth of A3AR agonist applicability in CIPN while investigating underlying protective mechanism(s) of action. Using IB-MECA, three Specific Aims will test our Central hypothesis: A3AR agonists are effective therapeutics in CIPN caused by chemotherapeutics with distinct antitumor mechanisms of action (paclitaxel, oxaliplatin & bortezomib) with beneficial effects exerted at the level of the peripheral sensory afferent (PSA) neuron &/or spinal cord. In Aim 1, we will test if 1) IB-MECA blocks and reverses neuropathic pain, 2) the effects of IB-MECA are specific to an A3AR mediated mechanism using pharmacological & genetic knockout approaches, 3) potential Central & peripheral site(s) of action underlie IB-MECA's action & 4) IB-MECA prevents chemotherapy-evoked degeneration of intraepidermal nerve fibers & primary afferent spontaneous discharge. In Aim 2, we will investigate the mechanism(s) whereby IB-MECA attenuates neuropathic pain through mitoprotective effects in PSA. Finally, in Aim 3, we will investigate if IB-MECA's effects include attenuating neuroinflammation &/or the dysregulation of glutamate homeostasis in the spinal cord, processes known to be essential to Central sensitization. We will focus on NF-κB & MAPK (ERK1/2, p38) signaling & glial-derived pro (TNF-α, IL-1β, and IL6)/anti (IL10)-inflammatory cytokines, as well as, the effects on the expression and activities of spinal glutamate transporters (neuronal & glial) and glial glutamine synthetase. If our hypothesis holds true, the outcome of our results are anticipated to provide the pharmacological rationale for "proof-of-concept" for the use of selective A3AR agonists as a new approach in CIPN. From a translational perspective, this could conceivably lead to a "fast track" investigation of IB-MECA for CIPN. This exciting possibility underscores the immediate clinical impact that our research proposal may have in this critical & unmet medical setting. Given the breadth of disorders impacted by A3AR agonists understanding their mechanism-based effects has far-reaching basic science & clinical implications.