The Role of Nitric Oxide In 7α,25-Dihydroxycholesterol-Induced Peripheral Sensitization

Neuropathic pain afflicts millions of people worldwide. Current pharmacological therapies for neuropathic pain have multiple side effects and limited efficacy; therefore, novel treatment targets are needed. Our group has identified GPR183 as a potential non-opioid-based target for the treatment of neuropathic pain. GPR183 is expressed by immune cells associated with neuropathic pain (e.g., macrophages and T cells). GPR183 plays a role in central sensitization through activity on microglia (Braden, 2020; Braden, 2022), and a recent study suggests possible roles in the periphery through macrophage localization in the skin (Chen, 2023). However, the role of GPR183 in peripheral sensitization is still not well understood and was the subject of our investigation. In rats, intraplantar injections of 7α,25-dihydroxycholesterol, the most potent ligand for GPR183, induced thermal hyperalgesia (up to 24 hours) and mechano-allodynia (up to 5 days). These behavioral hypersensitivities are blocked by a GPR183 antagonist, SAE14. No inherent signs of inflammation were observed in 7α,25-dihydroxycholesterol-treated paws. Blocking all isoforms of nitric oxide synthase (NOS) using L-NAME reduced acute mechano-allodynia and prevented long-term hypersensitivity. Prophylactic treatment with the selective iNOS inhibitor, L-NIL, attenuated acute mechano-allodynia with no effect on long-term hypersensitivity. Selective inhibition of nNOS with ARL 17477 had no effect on acute pain and reduced recovery from long-term hypersensitivity. Our results show that GPR183 signaling results in peripheral sensitization by engaging NOS signaling. Funded by the National Institutes of Health R01NS128004 and T32 GM141602-01 A1.