Nonopioid Chronic Pain Treatment by Erasing Spinal Pain Memory
Abstract
This project is to rigorously evaluate if activating spinal GPR37 (G protein-coupled receptor 37) has a potential of treating and preventing pain chronification by erasing “spinal pain memory” without posing a risk of abuse. Thus, this project addresses two FY20 CPMRP Investigator-Initiated Research Award Focus Areas, namely, the development of 1) novel non-mu-opioid receptor-targeted therapies for the treatment of chronic pain and 2) mechanistically justified therapies to prevent and treat pain chronification. In our preliminary experiments, inspired by previous studies showing pain-inhibitory effects of compounds later discovered as GPR37 agonists, we obtained evidence that activating GPR37 at the spinal level abolishes, not just temporarily suppresses as does morphine, long-lasting pain behaviors in animal models; these behaviors are reported to be associated with tissue injury-induced long-term changes (“memory”) in the spinal pain system. It should be noted here that only a few approaches (e.g., an extremely high dose of short-acting opioid remifentanil) have been shown to erase such long-term changes in the spinal pain system. Additionally, compared with repeated morphine administrations, repeated doses of spinal GPR37 activator showed no abuse liability in the preliminary study. The direct outcome of this project will be robust preclinical evidence indicating that spinal GPR37 activation abolishes an acute injury-induced long-lasting pain and facilitates the resolution of chronic neuropathic pain. This outcome has a significant implication for chronic pain treatment. Specifically, by exploiting the potential of spinal GPR37 activation, we may ultimately “erase” spinal pain memory underlying chronic pain and “reset” the hyperactive spinal pain system to baseline, effectively treating and preventing pain chronification. Therefore, the results of this project will contribute to advancing chronic pain research by stimulating new research into: 1) translational evaluation of the pain-relief efficacy of currently available GPR37 agonists in a spinal administration design; 2) elucidation of pain memory erasure mechanisms up/downstream of GPR37; and 3) development of selective activators of GPR37 for use in pain medicine. Successful translation of this project will generate a novel chronic pain therapy targeting spinal GPR37. For example, for patients who suffer acute injury (e.g., active military Service Members who are taken to hospitals after injury), GPR37 activators can be given to erase the injury-induced long-term changes in the spinal pain system, which will reduce the risk of pain chronification after the injury. For pain patients in a chronic state (e.g., Veterans who already developed chronic pain), repeated administrations of GPR37 activators will facilitate the resolution of the chronic pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110752
Entities
People
- Jun-Ho La
Organizations
- United States Army
- University of Texas Medical Branch