GPR37 activation erases spinal pain memory and resolves increased nociception in murine models

Area of Science:

• Neuroscience
• Pharmacology
• Pain Research

Background:

• Persistent pain arises from spinal pain memory, a long-term change in the spinal nociceptive system due to intense injury.
• Current treatments often fail to resolve chronic pain conditions effectively.

Purpose of the Study:

• To investigate if activating G protein-coupled receptor 37 (GPR37) in the spinal cord can erase spinal pain memory and alleviate long-lasting pain.
• To evaluate the therapeutic potential of GPR37 agonists for persistent pain.

Main Methods:

• Utilized capsaicin and hyperalgesic priming animal models.
• Administered GPR37 agonists (TX14A, PD1) intrathecally (i.th.).
• Assessed nociception, performed ex vivo Ca2+ imaging, and conducted conditioned place preference tests.
• Investigated the role of spinal GPR37 using global knockout mice.

Main Results:

• Single i.th. administration of GPR37 agonists dose-dependently inhibited acute and long-term nociception in the capsaicin model.
• GPR37 agonists prevented hypernociception in the hyperalgesic priming model, showing an 'unpriming' effect.
• Spinal GPR37 activation rescued dorsal horn neurons from altered responsiveness, suggesting erasure of pain memory.
• Global GPR37 knockout abolished these effects, confirming the receptor's role.
• No abuse liability was observed for centrally administered GPR37 agonists.

Conclusions:

• Spinal GPR37 agonism effectively erases spinal pain memory and resolves persistent pain.
• Targeting spinal GPR37 represents a novel therapeutic strategy for chronic pain management.
• This approach offers a promising way to treat pain by addressing its underlying memory mechanisms.