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Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

Lookup NU author(s): Dr Ilona Obara

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

Abstract

©2015 International Association for the Study of Pain. Activated mammalian target of rapamycin (P-mTOR) has been shown to maintain the sensitivity of subsets of small-diameter primary afferent A-nociceptors. Local or systemic inhibition of the mTOR complex 1 (mTORC1) pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In this study, we have investigated the effects of the rapamycin analog temsirolimus (CCI-779) on itch. Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 and histamine-independent pruritogens, chloroquine and SLIGRL-NH2, injected intradermally were significantly reduced by local (intradermal) or systemic (intraperitoneal, i.p.) pretreatment with CCI-779. We also investigated the action of metformin, a drug taken to control type 2 diabetes and recently shownto inhibitmTORC1in vivo. Although the response to nonhistaminergic stimuli was reduced at all of the time points tested, scratching to compound 48/80 wasmodified bymetformin only when the drugwas injected 24 hours before this pruritogen. We also examined the colocalization of P-mTOR with gastrin-releasing peptide, a putative marker for some itch-sensitive primary afferents, and found that P-mTORwas coexpressed in less than 5%of gastrin-releasing peptide-positive fibers in themouse skin. Taken together, the data highlight the role that P-mTOR-positive A-fibers play in itch signaling and underline the importance of the mTORC1 pathway in the regulation of homeostatic primary afferent functions such as pain and itch. The actions of the antidiabetic drug metformin in ameliorating nonhistamine-mediated itch also suggest a new therapeutic route for the control of this category of pruritus.

Publication metadata

Author(s): Obara I, Medrano MC, Signoret-Genest J, Jimenez-Diaz L, Geranton SM, Hunt SP

Publication type: Article

Publication status: Published

Journal: Pain

Year: 2015

Volume: 156

Issue: 8

Pages: 1519-1529

Print publication date: 01/08/2015

Acceptance date: 10/04/2015

Date deposited: 01/09/2017

ISSN (print): 0304-3959

ISSN (electronic): 1872-6623

Publisher: Lippincott Williams and Wilkins

URL: https://doi.org/10.1097/j.pain.0000000000000197

DOI: 10.1097/j.pain.0000000000000197

PubMed id: 25906350

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