Project Summary/Abstract Chronic pain affects 20% of the U.S. population, poses an enormous socioeconomical cost and remains an area of considerable unmet medical need. The opioid epidemics added urgency to develop novel and actionable therapeutic targets. We have identified a novel intercellular signaling system in spinal cord involving the multifunctional enzyme CD38 that may inform the development of new-generation analgesics and help solve this critical void. CD38 was first identified as an immune cell marker and is now widely recognized as a multifunctional enzyme that regulates cellular responses to chemical cues via the metabolism of nicotinamide adenine dinucleotide (NAD) into multiple mediators of calcium signaling. Using genetic and pharmacologic methods in mouse models of neuropathic and inflammatory pains, we generated evidence suggesting that CD38 expressed in astrocytes is part of an endogenous anti-nociceptive system in the spinal cord that is relevant to chronic pain. There is, therefore, a critical need to fully characterize and validate the role of CD38 and its metabolites in reducing hypersensitivity associated with peripheral nerve injury and inflammation. Our long-term goal is to understand the mechanism by which CD38 influences nociceptive signaling to develop novel pain therapies. Our overall objective in this application is to characterize how CD38 expression in the spinal cord mediates anti-nociception in mouse models of neuropathic and inflammatory pains. Our central hypothesis is that CD38-dependent signaling in the spinal cord can decrease hypersensitivity associated with peripheral nerve injury and inflammation. The rationale for the proposed studies is that characterizing the CD38 anti-nociceptive signaling could lead to novel therapeutic developments for chronic pain. In the absence of such knowledge, the realization of a CD38-centered strategy to treat chronic pain will remain uncertain. The following two specific aims will be pursued: 1) Validate CD38 as a target for opioid signaling in neuropathic and inflammatory pain models. 2) Characterize the anti-nociceptive properties, tolerance and reward liability of CD38-generated metabolites in neuropathic and inflammatory pains. For the first aim, we will use an integrated genetic and pharmacologic strategy in distinct pain models (spared nerve injury, SNI; complete Freund’s Adjuvant, CFA) to understand the role of CD38 in opioid signaling in the spinal cord. Under the second aim, we will use CD38-generated metabolites alone or in combination with opioids in the CFA and SNI pain models to determine the anti-nociceptive properties of the metabolites. The proposed exploratory research is innovative because it focuses on a novel endogenous antinociceptive spinal mechanism relevant to chronic pain with the advantage of improved authentication of pharmacological tools. The research is significant because it is expected to advance the mechanism-based understanding of spinal ...