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Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

ABSTRACT: Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated G?i signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca2+-independent protein kinase C (PKC)? from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKC? translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKC?-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies.

SUBMITTER: Munanairi A

PROVIDER: S-EPMC5937707 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

Munanairi Admire A Liu Xian-Yu XY Barry Devin M DM Yang Qianyi Q Yin Jun-Bin JB Jin Hua H Li Hui H Meng Qing-Tao QT Peng Jia-Hang JH Wu Zhen-Yu ZY Yin Jun J Zhou Xuan-Yi XY Wan Li L Mo Ping P Kim Seungil S Huo Fu-Quan FQ Jeffry Joseph J Li Yun-Qing YQ Bardoni Rita R Bruchas Michael R MR Chen Zhou-Feng ZF

Cell reports 20180401 3

Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated G<sub>αi</sub> signaling is not require ...[more]

PMID: 29669290

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Project description:BACKGROUND:Dry skin itch is one of the most common skin diseases and elderly people are believed to be particularly prone to it. The inflammasome has been suggested to play an important role in chronic inflammatory disorders including inflammatory skin diseases such as psoriasis. However, little is known about the role of NLRP1 inflammasome in dry skin-induced chronic itch. METHODS:Dry skin-induced chronic itch model was established by acetone-ether-water (AEW) treatment. Spontaneous scratching behavior was recorded by video monitoring. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes, transient receptor potential vanilloid type 1 (TRPV1), and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay (ELISA) kits. Nlrp1a knockdown was performed by an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. H.E. staining was used to evaluate skin lesion. RESULTS:AEW treatment triggers spontaneous scratching and significantly increases the expression of NLRP1, ASC, and caspase-1 and the levels of IL-1?, IL-18, IL-6, and TNF-? in the spinal cord and the skin of mice. Spinal cord Nlrp1a knockdown prevents AEW-induced NLRP1 inflammasome assembly, TRPV1 channel activation, and spontaneous scratching behavior. Capsazepine, a specific antagonist of TRPV1, can also inhibit AEW-induced inflammatory response and scratching behavior. Furthermore, elderly mice and female mice exhibited more significant AEW-induced scratching behavior than young mice and male mice, respectively. Interestingly, AEW-induced increases in the expression of NLRP1 inflammasome complex and the levels of inflammatory cytokines were more remarkable in elderly mice and female mice than in young mice and male mice, respectively. CONCLUSIONS:Spinal cord NLRP1 inflammasome-mediated inflammatory response contributes to dry skin-induced chronic itch by TRPV1 channel, and it is also involved in age and sex differences of chronic itch. Inhibition of NLRP1 inflammasome may offer a new therapy for dry skin itch.

Dataset Information

Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

Publications

Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

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