Peripheral ASIC1a regulation in an LPS-induced inflammatory pain model.

Animal models of inflammatory pain frequently rely on local administration of irritants that trigger acute inflammation and hypersensitivity. Lipopolysaccharide (LPS) is a well-established activator of innate immune pathways. Subcutaneous (intraplantar) injection of LPS into the hind paw produces a localized inflammatory reaction characterized by swelling, cellular infiltration, and increased mechanical and thermal sensitivity. Acid-sensing ion channels (ASICs) are key contributors to nociceptive signaling; however, their presence and regulation at the level of peripheral terminals, particularly in the skin, remain insufficiently characterized. We previously showed that formalin-induced acute pain increases ASIC1a expression in the central nervous system and peripheral dorsal root ganglia (DRGs). In this study, using the LPS paw model in both male and female mice, we demonstrate a robust upregulation of ASIC1a directly within inflamed paw tissue, together with changes in lumbar dorsal root ganglia (DRGs), which contain the somata of sensory neurons innervating the paw. We further show that ASIC1a upregulation is associated with paw edema, ERK activation, miRNA-dependent regulatory mechanisms, and the development of behavioral hypersensitivity induced by LPS. Importantly, local pharmacological blockade of ASIC1a with subcutaneous PcTx-1 attenuated both mechanical and thermal hypersensitivity. Together, our findings identify inflamed peripheral tissue as an important site of ASIC1a regulation during LPS-induced inflammation and provide new insight into the molecular mechanisms governing ASIC1a expression in inflammatory pain, supporting further exploration of ASIC1a-targeted therapeutic strategies.