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Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch.

ABSTRACT: Aim: Ample evidence indicates that gastrin-releasing peptide receptor (GRPR)-expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch-responsive GRPR⁺ neurons contribute to the spinal transmission of imiquimod (IMQ)-induced psoriatic itch.

Methods: To generate a psoriasis model, C57BL/6J mice received a daily topical application of 5% IMQ cream on their shaved back skin for 7-10 consecutive days. GRP⁺ neurons were inhibited using Cre-dependent expression of Gi-designer receptors exclusively activated by designer drugs (DREADDs), while GRPR⁺ neurons were ablated by intrathecal administration of bombesin-saporin.

Results: Repeated topical application of IMQ elicited psoriasis-like dermatitis and scratching behaviors. The mRNA expression levels of GRP and GRPR were upregulated in the cervical spinal dorsal horn (SDH) on days 7 and 10 after IMQ application. Either chemogenetic silencing of GRP⁺ neurons by Gi-DREADD or ablation of GRPR⁺ neurons significantly attenuated IMQ-induced scratching behaviors.

Conclusion: The GRP-GRPR system might be enhanced in the SDH, and itch-responsive GRPR⁺ neurons largely contribute to intractable itch in a mouse model of psoriasis.

SUBMITTER: Kiguchi N

PROVIDER: S-EPMC7722649 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch.

Kiguchi Norikazu N Saika Fumihiro F Fukazawa Yohji Y Matsuzaki Shinsuke S Kishioka Shiroh S

Neuropsychopharmacology reports 20200625 3

<h4>Aim</h4>Ample evidence indicates that gastrin-releasing peptide receptor (GRPR)-expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch-responsive GRPR<sup>+</sup> neurons contribute to the spinal transmission of imiquimod (IMQ)-induced psoriatic itch.<h4>Methods</h4>To generate a psoriasis model, C57BL/6J mice r ...[more]

PMID: 32584520

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Project description:Vesicular glutamate transporter-2 (VGluT2) mediates the uptake of glutamate into synaptic vesicles in neurons. Spinal cord dorsal horn interneurons are highly heterogeneous and molecularly diverse. The functional significance of VGluT2-expressing dorsal horn neurons in physiological and pathological pain conditions has not been explicitly demonstrated. Designer receptors exclusively activated by designer drugs (DREADDs) are a powerful chemogenetic tool to reversibly control neuronal excitability and behavior. Here, we used transgenic mice with Cre recombinase expression driven by the VGluT2 promoter, combined with the chemogenetic approach, to determine the contribution of VGluT2-expressing dorsal horn neurons to nociceptive regulation. Adeno-associated viral vectors expressing double-floxed Cre-dependent G?q-coupled human M3 muscarinic receptor DREADD (hM3D)-mCherry or G?i-coupled ?-opioid receptor DREADD (KORD)-IRES-mCitrine were microinjected into the superficial spinal dorsal horn of VGluT2-Cre mice. Immunofluorescence labeling showed that VGluT2 was predominantly expressed in lamina II excitatory interneurons. Activation of excitatory hM3D in VGluT2-expressing neurons with clozapine N-oxide caused a profound increase in neuronal firing and synaptic glutamate release. Conversely, activation of inhibitory KORD in VGluT2-expressing neurons with salvinorin B markedly inhibited neuronal activity and synaptic glutamate release. In addition, chemogenetic stimulation of VGluT2-expressing neurons increased mechanical and thermal sensitivities in naive mice, whereas chemogenetic silencing of VGluT2-expressing neurons reversed pain hypersensitivity induced by tissue inflammation and peripheral nerve injury. These findings indicate that VGluT2-expressing excitatory neurons play a crucial role in mediating nociceptive transmission in the spinal dorsal horn. Targeting glutamatergic dorsal horn neurons with inhibitory DREADDs may be a new strategy for treating inflammatory pain and neuropathic pain.

Dataset Information

Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch.

Publications

Critical role of GRP receptor-expressing neurons in the spinal transmission of imiquimod-induced psoriatic itch.

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