title: Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice.
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 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.
authors.affiliation: 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.
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Maria C
authors.initials: MC
authors.lastname: Medrano
authors.forename: Jérémy
authors.initials: J
authors.lastname: Signoret-Genest
authors.forename: Lydia
authors.initials: L
authors.lastname: Jiménez-Díaz
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Géranton
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019886:Gastrin-Releasing Peptide / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D019886:Gastrin-Releasing Peptide; D006632:Histamine; D008687:Metformin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus