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

Ilona Obara, Maria C. Medrano, Jérémy Signoret-Genest, Lydia Jiménez-Díaz, Sandrine M. Géranton, Stephen P. Hunt
Pain. 2015-08-01; 156(8): 1519-1529
DOI: 10.1097/j.pain.0000000000000197

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Obara I(1), Medrano MC, Signoret-Genest J, Jiménez-Díaz L, Géranton SM, Hunt SP.

Author information:
(1)Department of Cell and Developmental Biology, University College London,
London, United Kingdom School of Medicine, Pharmacy and Health, Durham
University, Stockton-on-Tees, United Kingdom Department of Pharmacology, Faculty
of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Bizkaia,
Spain Laboratorio de Neurofisiología y Comportamiento, Facultad de Medicina de
Ciudad Real, Universidad de Castilla-La Mancha, Castilla-La Mancha, Spain.

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 shown
to inhibit mTORC1 in vivo. Although the response to nonhistaminergic stimuli was
reduced at all of the 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 colocalization of P-mTOR with gastrin-releasing
peptide, a putative marker for some itch-sensitive primary afferents, and found
that P-mTOR was coexpressed in less than 5% of gastrin-releasing peptide-positive
fibers in the mouse 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.

DOI: 10.1097/j.pain.0000000000000197
PMID: 25906350 [Indexed for MEDLINE]

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