Myelinated mechano-nociceptors encode noxious cold and underlie hypersensitivity in pulpitis

Abstract

The ability to identify dangerous temperatures is critical, but the neural basis for cold sensation remains enigmatic. By combining in vivo functional imaging with tissue-specific spatiotemporal cooling, we unveil myelinated high threshold-mechanonociceptors (HTMRs) as the neural origin of tooth cold sensitivity. Critically, this neural encoding is driven by threshold noxious cold temperature, not cooling rate and remains independent of the cool receptor TRPM8 or pain transducer Nav1.8. Furthermore, while Bmpr1b-Cre captures the intradental HTMRs, it further reveals myelinated HTMRs mediate trigeminal cold encoding in soft tissues. Finally, we determine that inflammation potentiates intradental HTMRs, providing functional basis for clinical hypersensitivity in pulpitis. Collectively, our results reveal a new neural mediator of cold sensation and provide insight into painful transformation of cold sensory encoding in inflammation.