C-fiber low-threshold mechanoreceptors versus C-fiber nociceptors: distinct properties and signatures

Mammalian skin is innervated by distinct classes of low-threshold mechanoreceptors (LTMRs) and nociceptors, which are broadly categorized according to axonal conduction velocity into Aβ-, Aδ-and C-fiber populations. C-LTMRs encode innocuous mechanical stimuli and, in humans (where they are termed C-tactile [CT] afferents), contribute to affective/social touch, whereas nociceptors detect potentially tissue-damaging stimuli. For decades, C-LTMRs were thought to be confined to hairy skin. However, approximately a decade ago, we provided the first electrophysiological evidence for a rare population of C-LTMRs in rat glabrous skin. Subsequent human studies identified sparse CT afferents in the palm, indicating that C-LTMRs are present in glabrous skin in both rodents and humans, albeit far less frequently than in hairy skin. This review examines evidence supporting the presence and conservation of C-LTMRs across species in both hairy and glabrous skin, and that they are molecularly, anatomically, transcriptionally, and functionally distinct from C-fiber nociceptors, differing in their peripheral endings, central projections, receptive properties, and electrophysiological signatures. We also critically examine the proposed state-dependent role of C-LTMRs in injury-induced mechanical hypersensitivity, highlighting conflicting evidence from VGLUT3-based studies and emphasizing that their causal contribution to pathological pain remains unresolved. In contrast, under homeostatic conditions, C-LTMRs may instead engage inhibitory spinal microcircuits and release anti-nociceptive mediators, such as TAFA4, that help limit hypersensitivity. We summarize the ion channels and neurochemical markers that distinguish C-LTMRs from C-nociceptors and discuss how failure to recognize these distinct afferent populations may lead to misinterpretation of somatosensory and pain-related findings.