Activation of G-protein-coupled receptor 183 initiates inflammatory pain via macrophage CCL22 secretion

Chronic pain is a major public health problem with limited effective therapeutic options. G-protein-coupled receptors play a significant role in pain modulation; however, whether and how G-protein-coupled receptor 183 participates in pain regulation remain unclear. In the present study, we found that G-protein-coupled receptor 183 expression was specifically upregulated in the hind paws of mice in various inflammatory pain models. Activation of G-protein-coupled receptor 183 induced acute pain, whereas inhibition or silencing of this receptor alleviated mechanical allodynia and thermal hyperalgesia in complete Freund's Adjuvant (CFA) model. Mechanistically, activating G-protein-coupled receptor 183 triggers pain responses via the upregulation of C-C motif chemokine 22(CCL22) in macrophages while blocking the CCL22 receptor C-C motif Chemokine Receptor 4 (CCR4) attenuates pain hypersensitivity. Taken together, our findings indicate that the G-protein-coupled receptor 183-CCL22 axis has a critical role in the development and maintenance of inflammatory pain.