GPR183-Oxysterol Axis in Spinal Cord Contributes to Neuropathic Pain

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Neuropathic pain is a significant public health issue requiring non-narcotic treatments.
• G protein-coupled receptor 183 (GPR183), a chemotactic receptor, is upregulated in the spinal cord after nerve injury.
• The role of GPR183 in the central nervous system and pain pathways is largely unknown.

Purpose of the Study:

• To investigate the role of GPR183 in neuropathic pain.
• To identify novel small-molecule antagonists for GPR183.
• To evaluate the therapeutic potential of GPR183 antagonists for pain management.

Main Methods:

• Transcriptomic screening of spinal cord tissue after nerve injury.
• In silico screening of a compound library to identify GPR183 antagonists.
• In vitro assessment of antagonist potency using calcium mobilization assays.
• In vivo evaluation of antagonist efficacy in rodent models of neuropathic pain.

Main Results:

• GPR183 was found to be upregulated in the spinal cord following nerve injury.
• Novel GPR183 antagonists with nanomolar potency were identified.
• Intrathecal administration of these antagonists reversed allodynia in neuropathic pain models.
• Activation of spinal GPR183 by its ligand induced allodynia, which was blocked by antagonists.

Conclusions:

• Spinal GPR183 signaling plays a pronociceptive role in neuropathic pain.
• Novel GPR183 antagonists demonstrate therapeutic potential for treating neuropathic pain.
• GPR183 represents a promising novel target for non-narcotic pain therapeutics.