EXPLORING THE ROLE OF ASIC1 CHANNELS IN PAIN PERCEPTION: INSIGHTS FROM A FABRY MOUSE MODEL

GEORGINA ORIANA MINGOLO MALNATI; MAYRA MICAELA MONTES; CASTELLANOS, LIBIA C SALINAS; OSVALDO DANIEL UCHITEL; CARINA WEISSMANN

Buenos Aires

Congreso; VI International Congress in Translational Medicine; 2023

VI International Congress in Translational Medicine

Ion channels play a key role in the intricate pain pathway, encompassing the detection of localized stimuli, the transmission of electrical impulses to the brain, and the interpretation of these impulses as pain signals. Acid-sensing ion channels (ASICs) stand out as sensors intricately involved in neural modulation within the central nervous system and the perception of pain-associated tissue acidosis within the peripheral system. Remarkably, upregulation of ASIC1 channels has been extensively documented across a spectrum of pathological conditions. Our previous studies, conducted in HEK293 cells and primary mouse neurons, unveiled that exposure to glycosphingolipids, mainly Gb3, found in Fabry disease (FD), upregulates ASIC1a. In the present work, we analyzed an FD mouse model (alpha galactosidase knock-out mouse, GlaKO), characterized by Gb3 accumulation. GlaKO mice exhibited increased mechanical sensitivity relative to their wild-type (WT) counterparts, as evidenced by von Frey experiments. These behavioral changes correlated with increased ASIC1 expression levels in key pain-related regions, including the spinal cord (SC), and Dorsal Root Ganglia (DRG), particularly in the lumbar regions. We also considered age and gender differences, finding that older and female mice had higher ASIC1 expression levels across all regions. This elevated expression correlated with increased ERK phosphorylation (pERK), indicating specific signaling pathways' involvement in ASIC1 regulation.Furthermore, intrathecal administration of an ASIC1a inhibitor, Psalmotoxin-1 (Pctx-1), reduced mechanical sensitivity in GlaKO mice, accompanied by a decrease in pERK levels in the spinal cord.In summary, our study confirms altered ASIC1 channel expression in critical pain-related regions of the FD mouse model. These findings highlight the potential of ASIC1 as a therapeutic target for managing pain in Fabry Disease, offering valuable insights for future research and treatment strategies.