Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Koga, Katsumi; Yamagata, Ryo; Kohno, Keita; Yamane, Toshimi; Shiratori-Hayashi, Miho; Kohro, Yuta; Tozaki‐Saitoh, Hidetoshi; Tsuda, Makoto

doi:10.1016/j.jaci.2019.09.034

Cited by 34 publications

(46 citation statements)

References 40 publications

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“…Activation of the GRPRexpressing cells depended on both a glutamatergic synaptic mechanism, and simultaneous action of GRP on the GRPR, and this connection is thought to be part of the spinal cord circuit for itch, conveying information from pruritoceptors via these two classes of interneuron (secondary and tertiary pruritoceptors) to anterolateral tract (ALT) projection neurons in lamina I 7,9 . However, a recent study 55 identified GRPR neurons as vertical cells, and this is consistent with our observations from a GRPR CreERT2 mouse line 41 (MG-M, EP, AMB, AJT, unpublished data). Two independent groups have shown that GRP-eGFP cells correspond to a population identified by Grudt and Perl 24 as transient central cells 3,19,20 .…”

Section: Discussionsupporting

confidence: 92%

Expression of green fluorescent protein defines a specific population of lamina II excitatory interneurons in the GRP::eGFP mouse

Bell

Gutièrrez‐Mecinas

Stevenson

et al. 2020

Sci Rep

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Dorsal horn excitatory interneurons that express gastrin-releasing peptide (GRP) are part of the circuit for pruritogen-evoked itch. They have been extensively studied in a transgenic line in which enhanced green fluorescent protein (eGFP) is expressed under control of the Grp gene. The GRP-eGFP cells are separate from several other neurochemically-defined excitatory interneuron populations, and correspond to a class previously defined as transient central cells. However, mRNA for GRP is widely distributed among excitatory interneurons in superficial dorsal horn. Here we show that although Grp mRNA is present in several transcriptomically-defined populations, eGFP is restricted to a discrete subset of cells in the GRP::eGFP mouse, some of which express the neuromedin receptor 2 and likely belong to a cluster defined as Glut8. We show that these cells receive much of their excitatory synaptic input from MrgA3/MrgD-expressing nociceptive/pruritoceptive afferents and C-low threshold mechanoreceptors. Although the cells were not innervated by pruritoceptors expressing brain natriuretic peptide (BNP) most of them contained mRNA for NPR1, the receptor for BNP. In contrast, these cells received only ~ 10% of their excitatory input from other interneurons. These findings demonstrate that the GRP-eGFP cells constitute a discrete population of excitatory interneurons with a characteristic pattern of synaptic input. Neuronal circuits in the spinal dorsal horn process somatosensory information, which is then transmitted to the brain by projection cells. The vast majority of dorsal horn neurons are interneurons, and these can be assigned to two main classes: excitatory and inhibitory cells 1,2. Nociceptive and pruritoceptive primary afferents terminate in the superficial dorsal horn (SDH; laminae I-II), and ~ 75% of neurons in this region are excitatory interneurons 2. Recent studies have shown that these cells can be assigned to several largely non-overlapping populations, based on the expression of different neuropeptides 3-6 , and these are thought to have distinct roles in pain and itch. There is compelling evidence that gastrin-releasing peptide (GRP) and its receptor (GRPR) play a key role in itch. Intrathecal administration of GRP evokes scratching, while GRPR antagonists reduce scratching in response to pruritogens 7-11. In addition, mice lacking GRPR, or those in which GRPR-expressing dorsal horn neurons are ablated, show reduced responses in several itch models 7,8,12,13. Excitatory interneurons within the SDH provide a source of GRP 7,14-16 , and several studies have investigated the role of these cells by using BAC transgenic mouse lines from the GENSAT project 17 in which either enhanced green fluorescent protein (eGFP) 7,14,15,18-20 or Cre recombinase 18-21 is expressed under control of the Grp promoter

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Section: Discussionsupporting

confidence: 92%

Expression of green fluorescent protein defines a specific population of lamina II excitatory interneurons in the GRP::eGFP mouse

Bell

Gutièrrez‐Mecinas

Stevenson

et al. 2020

Sci Rep

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“…However, this is not surprising because our previous studies have shown that mice expressing a constitutive active form of STAT3 in spinal astrocytes do not exhibit spontaneous itchlike behaviors (biting and scratching) 16 and that LCN2 alone does not induce scratching (when given intrathecally in naive mice) 11 and has no effect on basal excitability of itchtransmission SDH neurons. 12 Given that LCN2 is capable of enhancing both neuronal excitation and scratching behavior evoked by gastrin-releasing peptide 11,12 (GRP), which is an itch inducer in the SDH, 2,3 it seems likely that spinal IL-6 or astrocytic STAT3 activation might produce scratching behavior in a condition wherein spinal GRP-GRP receptor signaling is active. 11 In addition, a recent study reported that spinal IL-33 is involved in activation of STAT3 in SDH astrocytes in a model of chronic itch associated with allergic contact dermatitis.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] We have recently demonstrated that astrocytes in the spinal dorsal horn (SDH) are activated in models of atopic and contact dermatitis and that reactive astrocytes and their released inflammatory factor lipocalin-2 (LCN2) are necessary for chronic itch. 11,12 The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the reactive process of astrocytes. 9 Indeed, pharmacologic and genetic inhibition of STAT3 suppresses reactive states of astrocytes in models of chronic itch.…”

mentioning

confidence: 99%

Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice

Shiratori-Hayashi

Chiharu

Eguchi

et al. 2021

Journal of Allergy and Clinical Immunology

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“…This enhanced itch in AD model mice was inhibited by prior intrathecal administration of a compound that inhibited STAT3 activation to the same extent as in control mice 32 . Furthermore, lipocalin 2 (LCN2), a humoral factor upregulated in an astrocytic STAT3‐dependent manner during chronic itch, enhanced both itch and GRPR‐positive neuronal excitability induced by GRP when co‐treated with GRP, whereas LCN2 alone did not increase both scratching and GRPR‐positive neuronal excitability 32,38 . AD and CD model mice with astrocytic STAT3 activation in the SDH showed significant upregulation of LCN2 in the SDH 32 .…”

Section: Activation Of Sdh Astrocytes and Spinal Sensitization For Itch During Chronic Itchmentioning

confidence: 96%

Spinal glial cells in itch modulation

Shiratori-Hayashi

Tsuda

2021

Pharmacology Res & Perspec

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Glial cells are non‐neuronal cells in the nervous system that are electrically non‐excitable and outnumber neurons in humans. Glial cells have attracted attention in recent years for their active involvement in the regulation of neuronal activity, suggesting their contribution to the pathogenesis and progression of neurological diseases. Studies have shown that astrocytes, a type of glial cell, are activated in the spinal cord in response to skin inflammation and contribute to the exacerbation of chronic itch. This review summarizes the current knowledge about the role of astrocytes and other glial cells in the modulation of itch processing and the mechanism of their activation under itch conditions.

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Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor

Cited by 34 publications

References 40 publications

Expression of green fluorescent protein defines a specific population of lamina II excitatory interneurons in the GRP::eGFP mouse

Expression of green fluorescent protein defines a specific population of lamina II excitatory interneurons in the GRP::eGFP mouse

Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice

Spinal glial cells in itch modulation

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