Research Paper

Chronic itch impairs mood and HPA axis function in mice: modulation by CRFR1 antagonist

Zhao, Xin^a,*; Yu, Chao^b; Ye, Feng^c; Wang, Yan-Gui^d; Mei, Qi-Yong^e; Ma, Qing^a; Cui, Wu-Geng^a; Zhou, Wen-Hua^a

^aDepartment of Pharmacology, School of Medical Science, Ningbo University, Ningbo, China

^bDepartment of Laboratory Medicine, The Second Hospital, Shandong University, Jinan, China

^cKey Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education of China, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

^dDepartment of Geriatrics, Hunan Provincial People's Hospital, Changsha, China

^eDepartment of Neurosurgery, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China

^*Corresponding author. Address: Department of Pharmacology, School of Medical Science, Ningbo University, 88 Feng-hua Rd, Ningbo 315211, Zhejiang, China. Tel.: +86-0574-87609608; fax: +86-0574-87609608. E-mail address: [email protected] (X. Zhao).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

PAIN 159(11):p 2201-2213, November 2018. | DOI: 10.1097/j.pain.0000000000001319

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Chronic itch is clinically correlated with the development of mood disorders such as anxiety and depression. Nonetheless, whether this relevance exists in rodents is unknown, and evidence demonstrating chronic itch can affect mood is lacking. The aim of this study is to characterize the affective consequences of chronic itch, and explore potential mechanisms and interventional strategy. We subjected mice to chronic itch by repetitive cutaneous treatment with acetone and diethylether followed by water (AEW) that models “dry skin.” After 3 to 4 weeks AEW treatment, the mice developed behavioral phenotypes of anxiety and depression assessed by a battery of behavioral paradigms, such as light–dark box and forced swim test. These behavioral symptoms of mood disturbance were independent of cutaneous barrier disruption, but correlated well with the degree of the irritating itch sensation. Although AEW mice showed normal circadian hypothalamic-pituitary-adrenal (HPA) axis activity, their neuroendocrine functionality was dampened, including impaired endocrine stress responsivity, altered neuroendocrine–immune interaction, and blunted corticosterone response to both dexamethasone and CRF. Parameters of HPA functionality at the level of mRNA transcripts are altered in stress-related brain regions of AEW mice, implying an overdrive of central CRF system. Remarkably, chronic treatment of AEW mice with antalarmin, a CRFR1 antagonist, ameliorated both their mood impairment and stress axis dysfunction. This is the first evidence revealing mood impairment, HPA axis dysfunction, and potential therapeutic efficacy by CRFR1 antagonist in mice with chronic itch, thus providing a preclinical model to investigate the affective consequence of chronic itch and the underlying mechanisms.