Dataset Information

Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch.

ABSTRACT: 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+) A? 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.

SUBMITTER: Pan H

PROVIDER: S-EPMC6763390 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch.

Pan Haili H Fatima Mahar M Li Alan A Lee Hankyu H Cai Wei W Horwitz Lorraine L Hor Chia Chun CC Zaher Nizam N Cin Mitchell M Slade Hannah H Huang Tianwen T Xu X Z Shawn XZS Duan Bo B

Neuron 20190716 6

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<sup>+</sup>) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mech ...[more]

PMID: 31324538

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Project description:Chronic itch is associated with sensitization of the somatosensory nervous system. Recent studies have identified the neural circuits transmitting acute itch; however, the mechanisms by which itch transforms into a pathological state remain largely unknown. We have previously shown that Aβ low-threshold mechanoreceptors, together with spinal urocortin 3-positive (Ucn3+) excitatory interneurons and neuropeptide Y-positive (NPY+) inhibitory interneurons, form a microcircuit that transmits and gates acute mechanical itch. Here, using whole-cell patch-clamp recordings, we observed increased excitability in spinal Ucn3+ neurons under chronic itch conditions. In contrast to Ucn3+ neurons, the excitability of spinal NPY+ neurons was largely reduced under chronic itch conditions. To explore the molecular mechanisms underlying sensitization of this microcircuit, we examined the mRNA expression levels of voltage-gated ion channels in recorded spinal Ucn3+ and NPY+ neurons by single-cell quantitative real-time PCR (qRT-PCR). We found that the expression levels of Nav1.6 and Cav2.3 channels were increased in spinal Ucn3+ neurons in chronic itch mice, while the expression level of SK3 channels was decreased. By contrast, the expression levels of Nav1.6 and BK channels were decreased in spinal NPY+ neurons in chronic itch mice. To determine the contribution of different ion channels in chronic itch sensitization, we then used a Markov Chain Monte Carlo method to parameterize a large number of biophysically distinct multicompartment models of Ucn3+ and NPY+ neurons. These models included explicit representations of the ion channels that we found to be up- or down-regulated under chronic itch conditions. Our models demonstrated that changes in Nav1.6 conductance are predominantly responsible for the changes in excitability of both Ucn3+ and NPY+ neurons during chronic itch pathogenesis. Furthermore, when simulating microcircuits of our Ucn3+ and NPY+ models, we found that reduced Nav1.6 conductance in NPY+ models played a major role in opening the itch gate under chronic itch conditions. However, changing SK, BK, or R-type calcium channel conductance had negligible effects on the sensitization of this circuit. Therefore, our results suggest that Nav1.6 channels may play an essential role in mechanical itch sensitization. The findings presented here may open a new avenue for developing pharmaceutical strategies to treat chronic itch.

Dataset Information

Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch.

Publications

Identification of a Spinal Circuit for Mechanical and Persistent Spontaneous Itch.

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