| Summary: | Increasing pre-clinical evidence supports a role of neuronal-immune interactions in chronic pain. Here, we investigated the involvement of G-protein receptor 84 (GPR84), an immune cell receptor that is markedly induced in monocytes/macrophages and microglia under inflammatory conditions, in chronic pain signalling. GPR84 knock-out (KO) mice exhibited normal acute pain thresholds but showed deficits in neuropathic and inflammatory pain responses. Thus, in contrast to wild-type (WT) mice, KOs did not develop mechanical allodynia or thermal hyperalgesia subsequent to partial sciatic nerve ligation (PNL) and exhibited attenuated mechanical, thermal and cold hyperalgesia after intraplantar injection of complete Freund’s adjuvant (CFA). Nerve injury or inflammation also resulted in increased Iba1 and phosphorylated p38 mitogen-activated protein kinase (MAPK) immunoreactivity in spinal microglia, as well as increased Iba1 expression in macrophages of the sciatic nerve post PNL, with no difference between genotypes. In WT mice, GPR84 mRNA expression was up-regulated in the spinal cord and sciatic nerve at 7 and 21 days post PNL, as well as in microglia or macrophage cultures at 3 hours post lipopolysaccharide (LPS) stimulation. Concurrent with these changes, we identified 86 dysregulated genes in the sciatic nerve and spinal cord following injury and 30 dysregulated mediators in macrophages following treatment. Interestingly, expression of arginase-1 (ARG1), a marker for anti-inflammatory macrophages, was considerably up-regulated by 20.8-fold in KO sciatic nerve at 7 days post PNL. In addition, forskolin-induced levels of 3'- 5'-cyclic adenosine monophosphate (cAMP) were greater in KO than WT macrophages. Together these data are indicative of an anti-inflammatory macrophage phenotype in KO mice under pathological conditions. We suggest that GPR84 is a pro-inflammatory receptor involved in nociceptive signalling in animal models of persistent pain, possibly mediating its effects via the modulation of peripheral macrophages. Based on these results GPR84 may be a promising new target with therapeutic potential in chronic pain.
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