Neuropathic pain, resulting from nerve injury or inflammation, affects approximately 4 million people in the USA alone (1) and remains poorly managed by currently available therapeutics. Most of these therapeutics specifically target neurons. However, it is now known that spinal glia (astrocytes and microglia) play an important role in facilitating and maintaining neuropathic pain in animal models (2). We have identified a novel therapeutic target in adenosine 2A receptors that modulate the immune cells within the CNS such that they switch from a classically pro-inflammatory state to an alternatively activated IL-10 generating state. The behavioral outcome of such a phenotypic switch results in a reversal of allodynia induced by neuropathic injury in rats for at least 4 wks from a SINGLE bolus administration. The purpose of this grant is to provide further evidence that this remarkable therapeutic effect can be translated to numerous animal models of neuropathic pain and to elucidate the underlying mechanisms that result in the production of IL-10 and subsequent reversal of the allodynia.