ABSTRACT Intense nociceptor inputs produce long-term changes in the spinal cord dorsal horn, which resemble the memory engram in the brain. Thus, such long-term changes are suggested to constitute ‘spinal pain memory’ underlying chronic pain. Efforts to develop chronic pain therapies targeting ‘pain memory maintenance’ have been unsuccessful due to our incomplete understanding of mechanisms maintaining this memory. Here we take a conceptually novel approach of triggering endogenous ‘pain memory erasure’ mechanisms for effective prevention and treatment of chronic pain. Based on the literature and our preliminary data demonstrating that activating the spinal G protein-coupled receptor 37 (GPR37) using its putative agonists reverses spinal long- term synaptic potentiation and abolishes/curtails long-lasting pain hypersensitivity in multiple animal models, we propose that spinal GPR37 is the key to erasing spinal pain memory and therefore, its agonists will be promising pain therapeutics effectively prevent/treat chronic pain. This project is to collect preliminary data validating this idea from pain biology, drug addiction, and drug discovery/development perspectives through the following Specific Aims. In Aim 1, using TX14A, a putative peptide agonist for GPR37, we will validate spinal GPR37 as a molecular target for pain therapy and identify cells expressing the receptor to mediate the pain memory erasure effect. Additionally, we will determine if TX14A reverses experimentally induced long-term changes in dorsal horn neuronal responses to afferent inputs. In Aim 2, we will develop a GPR37 cellular assay system and perform a high throughput screening (HTS) testing compounds in small molecule libraries to identify potential druggable GPR37 agonists. Using medicinal chemistry approaches, we will also design, synthesize, and early optimize new small peptide and peptidomimetic small molecules based on TX14A and the GPR37 HTS ‘hits’. In Aim 3, we will develop and optimize preclinical in vivo testing paradigms to streamline the assessment of analgesic efficacy and abuse liability of new GPR37 agonists. The preliminary results obtained through these Aims will lay the groundwork for a subsequent Team Research U19 application responding to RFA-NS-21-015. Specifically, the results of Aims 1-3 will be the basis of the three Research Components in the U19 application: 1) Validation of Therapeutic Target and Underlying Biology, 2) Assay Development, Screening and Optimization, and 3) Development and Validation of Animal Models and/or Outcome Measures.

NARRATIVE After tissue injury, sensory neural circuits in the spinal cord develop long-term changes similar to memory engram in the brain, constituting ‘spinal pain memory’ underlying chronic pain. In this project, proposing that the spinal G protein-coupled receptor 37 (GPR37) is the key to erasing this memory, we will collect preliminary data as a multidisciplinary research team to lay the groundwork for future research activities developing non-opioid pain therapeutics selectively and potently activating the receptor.