GRPR/pERK and NPRA/pERK: Partners in Central Transmission of Chronic Itch

Abstract

Background: Recurrent and intractable chronic itch is a world-wide problem but mechanisms, especially the neural mechanisms, underlying chronic itch still remain unclear. In this study, we investigated the peripheral and spinal mechanisms responsible for prolonged itch in a mouse model of allergic contact dermatitis induced by squaric acid dibutylester (SADBE). Methods: Behavioral tests in combination to genetic, pharmacological, neurotoxic approaches were performed on mouse models. Immunohistochemistry, RNAscope in situ hybridization assay, quantitative RT-PCR, multiplex Luminex assay and western blot were performed using mouse tissues. Western blot analysis also performed using transfected HEK293T cells as well. Findings: We found that repeated exposure of mice to SADBE evoked persistent spontaneous scratching lasting for weeks. SADBE-induced prolonged itch requires both histaminergic and nonhistaminergic pathways and is relayed by gastrin-releasing peptide receptor (GRPR) and natriuretic peptide receptor A (NPRA) in the spinal cord. We showed sustained extracellular signal-regulated kinase phosphorylation (pERK) in the spinal cord and its importance for prolonged itch. Both in vivo and in vitro analysis demonstrated that ERK is the primary downstream pathway of spinal itch receptors like GRPR, NPRA, somatostatin receptor sst2A and Neuromedin B receptor (NMBR). Interpretation: In spinal cord neural circuits, ERK activation exhibits considerable heterogeneity but plays a central role for chronic itch. Funding Statement: This work was supported by the National Natural Science Foundation of China under Grants 81301948, the National Science and Technology Major Project of China (2016ZX08011-005) and the Guangzhou science and technology project (201804020042). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All animal experiments were performed under protocols approved by the Animal Studies Committee of Guangzhou Medical University.