A central neural circuit for itch sensation

Mu, Di; Deng, Juan; Liu, Kefei; Wu, Zhenyu; Shi, Yufeng; Guo, Weimin; Qu, Yi; Liu, Xingjun; Li, Hui; Sun, Yan-Gang

doi:10.1126/science.aaf4918

Cited by 200 publications

(198 citation statements)

References 41 publications

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“…Therefore, CGRP PBN neurons can be activated by non-painful noxious stimuli and their activation is required to elicit appropriate behavioral responses. These findings identify a specific population of PBN neurons that contribute to itch-related behavior 20 .…”

Section: Resultsmentioning

confidence: 72%

Encoding of danger by parabrachial CGRP neurons

Campos

Bowen

Roman

et al. 2018

Nature

252

275

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Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide (CGRP) in the parabrachial nucleus (PBN) relay sensory signals that contribute to satiation and pain-induced fear behavior, but it is unknown how they encode these distinct processes. By recording calcium transients in vivo from individual CGRPPBN neurons, we reveal that most neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). These same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRPPBN neurons prevent overeating. CGRPPBN neurons are also activated during consumption of novel food or by an auditory cue that was previously paired with electrical foot shocks. Correspondingly, silencing CGRPPBN neurons attenuates expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRPPBN neurons promote affective-behavioral states that limit harm in response to potential threats.

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Section: Resultsmentioning

confidence: 72%

Encoding of danger by parabrachial CGRP neurons

Campos

Bowen

Roman

et al. 2018

Nature

252

275

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“…In recent years, great progress has been made toward understanding itch‐related neuronal circuitry. A growing body of literature has demonstrated that the peripheral nervous system, including TRPV1‐positive (Imamachi et al, ) and TRPA1‐positive (Wilson et al, ) primary afferent neurons, central neural circuits, including GRPR (Sun & Chen, ) positive neurons and the spinothalamic tract (Andrew & Craig, ), as well as the spinoparabrachial pathway (Mu et al, ), all contribute to itch. In addition to the neuronal basis of the itch sensation, astrocytes are considered new players in chronic itch.…”

Section: Discussionmentioning

confidence: 99%

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Yang

et al. 2019

Glia

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Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

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“…3 GRPR neurons may form contacts with NK1R neurons which project to the parabrachial nucleus (PBN) and the spinothalamic track (STT) neurons to relay itch information in mice (Akiyama et al, 2015;Cameron et al, 2015;Mu et al, 2017). Although some information about GRPR neurons have been obtained using indirect approaches or transgenic mice which may not fully recapitulate Grpr expression in the spinal cord (Aresh et al, 2017;Wang et al, 2013), direct characterization of molecular, anatomical and electrophysiological properties of GRPR neurons are yet to be achieved.…”

Section: Introductionmentioning

confidence: 99%

Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

Bardoni

Barry²,

et al. 2018

Preprint

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A myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.HighlightsActivation of GRPR neurons evokes itch and is dependent upon NK1R activationGRPR neurons receive both direct and indirect inputs from C/Aδ fibersCounter-stimuli inhibit GRPR neurons via GABAergic signalingIncreased excitability of GRPR neurons in chronic itch condition

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A central neural circuit for itch sensation

Cited by 200 publications

References 41 publications

Encoding of danger by parabrachial CGRP neurons

Encoding of danger by parabrachial CGRP neurons

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

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