Adipose-Derived miR-133a-3p And Its Role in Mechanical Sensitivity in Chronic Primary Pain Conditions
The Journal of Pain(2024)
摘要
To identify pain-relevant miRNAs downstream of beta adrenergic receptor (βAR) activation and determine their functional effects in chronic primary pain conditions (CPPCs). Rats received peripheral delivery of the β2- and β3AR antagonists ICI-118,511 (1.5mg/kg/day) and SR59230A (1.67 mg/kg/day) alongside systemic delivery of the catechol-o-methlytransferase inhibitor OR486 (15mg/kg/day) or vehicle over 14 days (N=20). RNA sequencing shows that OR486 treatment decreased levels of miR-133a in circulation, and this downregulation was prevented by βAR antagonism. miR-133a downregulation was replicated in acute (N=32) and sustained (N=23) CPPC mice and in human cohorts of vestibulodynia (N=75) and fibromyalgia (N=48) patients. qPCR in peripheral (adipose, muscle) and central (spinal cord) tissues collected from CPPC mice indicates that miR-133a was downregulated in adipose at both times, while in the spinal cord there was differential expression only at the 14-day time point. Further, β3AR activation in primary adipocytes drives miR-133a downregulation (N=15). We then induced adipose-specific overexpression of miR-133a to directly test its role in modulating pain. Compared to CPPC mice receiving a nonsense sequence, those treated with adipose-specific miR-133a exhibit significant increases in mechanical pain thresholds at multiple body sites, indicative of widespread analgesia (N=51). Further, miR-133a overexpression in primary dorsal root ganglion cultures had anti-nociceptive effects on capsaicin-induced phosphorylation of extracellular signal-regulated kinase (N=12) and capsaicin-induced calcium responses (N=32). These data provide the first link between miR-133a and CPPCs across species and support the use of peripherally-targeted miR-133a overexpression strategies for the treatment of CPPCs. Funding: NIH/NINDS R03NS106166 and R01NS109541 A Nackley. NIH/NIGMS T32GM133352 and NIH/NINDS F31NS130861 to N Hernandez.
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