Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-09, Vol.103 (6), p.1135-1149.e6
• Main Authors: Pan, Haili, Fatima, Mahar, Li, Alan, Lee, Hankyu, Cai, Wei, Horwitz, Lorraine, Hor, Chia Chun, Zaher, Nizam, Cin, Mitchell, Slade, Hannah, Huang, Tianwen, Xu, X.Z. Shawn, Duan, Bo
• Format: Article
• Language: English
• Subjects: Animals; Central Nervous System Sensitization - physiology; Excitability; Glutamic Acid - metabolism; Interneurons; Interneurons - metabolism; Interneurons - physiology; Mechanoreceptors; Mechanoreceptors - metabolism; Mechanoreceptors - physiology; Mice; Neural Inhibition - physiology; Neural networks; Neural Pathways - physiopathology; Neurons; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptides; Pain; Peptides; Physical Stimulation; Physiology; Pruritus - physiopathology; Skin; Skin - innervation; Spinal cord; Spinal Cord - cytology; Spinal Cord - physiopathology; Statistical analysis; Studies; TLR5 protein; Toll-Like Receptor 5 - metabolism; Toll-like receptors; Urocortin; Urocortins - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.06.016

Lightly stroking the lips or gently poking some skin regions can evoke mechanical itch in healthy human subjects. Sensitization of mechanical itch and persistent spontaneous itch are intractable symptoms in chronic itch patients. However, the underlying neural circuits are not well defined. We identified a subpopulation of excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mechanical itch sensitization as well as persistent spontaneous itch under chronic itch conditions. This population receives peripheral inputs from Toll-like receptor 5-positive (TLR5+) Aβ low-threshold mechanoreceptors and is directly innervated by inhibitory interneurons expressing neuropeptide Y::Cre (NPY+) in the dorsal spinal cord. Reduced synaptic inhibition and increased intrinsic excitability of Ucn3+ neurons lead to chronic itch sensitization. Our study sheds new light on the neural basis of chronic itch and unveils novel avenues for developing mechanism-specific therapeutic advancements. [Display omitted] •Spinal Ucn3+ neurons transmit both mechanical itch and persistent spontaneous itch•Spinal Ucn3+ neurons receive inputs from TLR5+ LTMRs•Spinal NPY+ inhibitory interneurons gate Ucn3+ neurons•Sensitization of mechanical itch pathway contributes to chronic itch Pan et al. identify a microcircuit in the dorsal spinal cord that transmit mechanically evoked itch. Sensitization of this pathway is required for chronic itch development.