Functional and molecular diversity of human C-fibers in pain modulation

Recent transcriptomic and microneurography studies have refined our understanding of human C-fiber diversity and function. This review summarizes knowledge of human C-low-threshold mechanoreceptors (C-LTMRs) and C-nociceptors, with emphasis on their molecular, physiological, and pathological roles in pain signaling and modulation, and discusses how these insights may inform therapeutic strategies targeting C-fibers.

Human single-cell transcriptomic studies have identified multiple distinct C-fiber populations with both conserved and human-specific features. Integration with microneurography has begun linking these molecular identities to functional phenotypes. Recent findings indicate that human C-LTMRs are polymodal afferents, responding to gentle touch as well as innocuous cooling and warming stimuli, whereas C-mechanoresponsive (CM) and C-mechanoinsensitive (CMi) nociceptors can develop features of peripheral sensitization under pathological conditions. Transcriptomic studies further reveal that molecular targets, such as transient receptor potential vanilloid 1, are shared across functionally distinct C-fiber classes, suggesting that analgesic therapies may act across broader and more functionally diverse C-fiber populations than traditionally appreciated.

Human C-fibers are highly heterogeneous and contribute to pain signaling through diverse and context-dependent mechanisms. Integration of transcriptomics with microneurography provides a framework for linking molecular identity with physiological function in humans and may facilitate the development of selective approaches for targeting pain-relevant afferent populations.