G2A as a Threshold Regulator of Inflammatory Hyperalgesia Modulates Chronic Hyperalgesia

Abstract

Tissue injury, pathogen infection, and diseases are often accompanied by inflammation to release mediators that sensitize nociceptors and further recruit immune cells, which can lead to chronic hyperalgesia and inflammation. Tissue acidosis, occurring at the inflammatory site, is a major factor contributing to pain and hyperalgesia. The receptor G2 accumulation (G2A), expressed in neurons and immune cells, responds to protons or oxidized free fatty acids such as 9-hydroxyoctadecadienoic acid produced by injured cells or oxidative stresses. We previously found increased G2A expression in mouse dorsal root ganglia (DRG) at 90 min after complete Freund's adjuvant (CFA)-induced inflammatory pain, but whether G2A is involved in the inflammation or hyperalgesia remained unclear. In this study, we overexpressed or knocked-down G2A gene expression in DRG to explore the roles of G2A. G2A overexpression reduced the infiltration of acute immune cells (granulocytes) and attenuated hyperalgesia at 90 to 240 min after CFA injection. G2A knockdown increased the number of immune cells before CFA injection and prolonged the inflammatory hyperalgesia after CFA injection. G2A may serve as a threshold regulator in neurons to attenuate the initial nociceptive and inflammatory signals, modulating the chronic state of hyperalgesia.

Evolution of acid nociception: ion channels and receptors for detecting acid

“…In a neuropathic pain model, G2A −/− mice exhibit less mechanical hypersensitivity, however oxaliplatin, the drug used to manifest the model, was shown to increase levels of oxidized lipids which could sensitize TRPV1 via G2A and PKC dependent mechanisms [240]. By contrast, overexpression of G2A in mice reduced mechanical hypersensitivity following CFA-induced inflammation, while knockdown prolonged hyperalgesia [241]. Given that we have recently reported that the CFA model does not result in acidosis, this suggests protons are not agonizing G2A to confer the observed pain relief [55].…”

N‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132

“…16 Biological activity of N-acylglycines and oxidized fatty-acids coincides with GPR132 location, in lymphocytes, 17,18 monocyte-lineage cells including macrophages 19 and keratinocytes. 20 GPR132 is implicated in diverse functions including nociception, 21,22 positioning of macrophages at sites of inflamation, 19 haematopoiesis, 23 sensing oxidative stress, 20 regulating macrophage responses in a tumor microenvironment, 24 and microglial colonization from periphery into developing brain (in zebrafish 25 ). However, understanding of GPR132 function has been hampered because multiple other ligands have been published to activate GPR132, and selective pharmacological tools for functional studies have not been available.…”

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism

“…The enhanced monocyte and macrophage migration due to G2A deletion brought about elevated macrophage recruitment to the vessel wall, as previously reported in Ldlr –/– G2a –/– mice ( Bolick et al, 2007 ). G2A knockdown had also been reported to increase macrophages in mouse neurons and prolong inflammatory hyperalgesia ( Su et al, 2018 ). However, some mice reports stated no change in macrophage chemotaxis by G2A deletion in Ldlr knockouts ( Parks et al, 2005 ).…”