Conserved small RNA networks link inflammation to pain signaling in mice and men.

Inflammation can lead to pain, but the underlying mechanisms remain unclear. Here, we identify small non-coding RNA (sncRNA) signatures including microRNAs (miRs) and transfer RNA fragments (tRFs) that may drive inflammatory pain in both acute and chronic settings. Using lipopolysaccharide (LPS)-induced inflammation in murine trigeminal (sensory) and superior cervical (sympathetic) ganglia, we observed temporally distinct alterations in miR and tRF expression. These inflammatory changes overlapped with sncRNA profiles detected in fibromyalgia syndrome (FMS) patient blood cells and keratinocytes, identifying a conserved set of pain-related sncRNAs. Cross-species analyses revealed two oppositely correlated sncRNA clusters whose ratio distinguished inflammatory from control states and progressively increased during human nociceptor differentiation. Integrative transcriptomic analysis demonstrated that these sncRNAs interact with cholinergic and pain-related long RNAs, implicating them in regulatory pathways central to pain modulation. Validation in an independent dataset of human osteoarthritis synovium revealed that these sncRNAs enable segregating low from high pain in human subjects. Together, our findings reveal that specific miRs and tRFs act as conserved regulators of nociceptive signaling across species, tissues, and pain modalities. Further, this work suggests a new understanding of the molecular underpinnings of pain, and highlights the concept that mammalian pain- and cholinergic-related sncRNAs actively contribute to the shift from inflammation to peripheral nervous system pain, including fibromyalgia pain.