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Inhibition of the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway reduces itch behaviour in mice

Obara, IG; Medrano, CM; Signoret-Genest, J; Jiménez-Díaz, L; Geranton, SM; Hunt, SP; (2015) Inhibition of the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway reduces itch behaviour in mice. Pain , 156 (8) pp. 1519-1529. 10.1097/j.pain.0000000000000197. Green open access

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Abstract

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 mTORC1 pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In the present study, we have investigated the effects of the rapamycin analogue temsirolimus (CCI-779) on itch. Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 as well as histamine-independent pruritogens, chloroquine and SLIGRL-NH2, injected intradermally (i.d.) were significantly reduced by local (i.d.) or systemic (intraperitoneal, i.p.) pre-treatment with CCI-779. We also investigated the action of metformin, a drug taken to control type-2 diabetes and recently shown to reduce in vivo mTORC1. While the response to non-histaminergic stimuli was reduced at all time points tested, scratching to compound 48/80 was modified by metformin only when the drug was injected 24 hours before this pruritogen. We also examined the co-localization of P-mTOR with gastrin-releasing peptide (GRP), a putative marker for some itch-sensitive primary afferents, and found that P-mTOR was co-expressed in less than 5% of GRP-positive fibers in mouse skin. Taken together, the data highlights 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 anti-diabetic drug metformin in ameliorating non-histamine mediated itch also suggest a new therapeutic route for the control of this category of pruritus.

Type: Article
Title: Inhibition of the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway reduces itch behaviour in mice
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/j.pain.0000000000000197
Publisher version: http://dx.doi.org/10.1097/j.pain.0000000000000197
Language: English
Additional information: © 2015 International Association for the Study of Pain. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Mammalian target of rapamycin complex 1 (mTORC1), gastrin-releasing peptide (GRP), temsirolimus (CCI-779), metformin, itch, mice
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1466738
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