Analysis of 304 postmortem brains revealed distinct gene expression patterns in chronic pain sufferers, with over 2,000 differentially expressed genes concentrated in microglial cells of the basolateral amygdala. Two specific genes, B4GALT2 and VEGFB, showed altered activity in the dorsal anterior cingulate cortex, while the amygdala emerged as a central hub for pain-related molecular changes across different conditions including opioid use. The microglial findings align with established mouse models of pain, suggesting these immune-like brain cells drive neuroinflammatory processes that sustain chronic pain states. This represents a significant advance in understanding pain's molecular footprint, as previous neuroimaging studies identified brain regions involved in pain processing but couldn't pinpoint the cellular mechanisms. The concentration of genetic changes in amygdala microglia is particularly noteworthy given this region's role in emotional pain processing and fear conditioning. However, the postmortem approach cannot establish whether these gene expression changes cause chronic pain or result from it. The research also highlights potential sex differences in pain genetics, though the mechanisms remain unclear. These molecular signatures could eventually guide development of targeted therapies that address the underlying cellular dysfunction rather than merely masking pain symptoms.