Targeting GPR183 to reduce peripheral sensitization: evidence from rodent and human tissue analyses

Area of Science:

• Immunology
• Neuroscience
• Pharmacology

Background:

• Peripheral sensitization, involving immune mediators, drives inflammatory pain.
• G protein-coupled receptor 183 (GPR183) on immune cells influences their function, but its role in pain is unclear.
• GPR183 signaling impacts ERK and nitric oxide synthase (NOS), key pain pathway components.

Purpose of the Study:

• Investigate GPR183's role in peripheral sensitization and identify involved immune cells.
• Determine the contribution of NOS isoforms to GPR183-mediated pain.
• Evaluate GPR183 antagonism as a pain management strategy.

Main Methods:

• Administered GPR183 ligand (7α,25-OHC) and antagonist (SAE-14) in rat models.
• Utilized NOS inhibitors and knockout rats to assess NOS isoform involvement.
• Analyzed GPR183 expression in human post-surgical skin samples.
• Performed Langerhans cell (LC) ablation studies in mice.

Main Results:

• 7α,25-OHC induced long-lasting nociception in rats, blocked by SAE-14.
• Both inducible and neuronal NOS isoforms contributed to 7α,25-OHC-induced sensitization.
• GPR183 expression increased in injured rat paws and human skin post-injury.
• Macrophages, not LCs, were identified as key GPR183-expressing cells driving hypersensitivity.

Conclusions:

• GPR183 signaling, involving NOS, mediates peripheral sensitization.
• GPR183 expression is upregulated following tissue injury in both rats and humans.
• GPR183 antagonism represents a potential therapeutic approach for managing inflammatory pain.