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.