title: Inhibition of phosphatidylinositol-3 kinase γ reduces pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice.
abstract: This study investigated the effects of pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K)γ in the pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice. The animals were orally treated with the selective PI3Kγ inhibitor AS605240 (0.3-30 mg/kg) 30 minutes beforehand. In separate groups, AS605240 was given by intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes. The control groups received saline at the same schedules. The effects of PI3K blocking were assessed in different experimental assays. The oral treatment with AS605240 produced a marked reduction of scratching behavior elicited by trypsin. Moreover, AS605240 (1mg/kg) was able to produce a partial but significant inhibition of the scratching bouts elicited by CP 48/80. Interestingly, the i.c.v. and i.t. injection of AS605240 also reduced trypsin-induced itching. The oral administration of AS605240 was found effective in producing a significant and dose-dependent reduction of trypsin-induced paw edema and tumor necrosis factor α production, as well as the neutrophil recruitment, according to myeloperoxidase activity assessment. Likewise, oral AS605240 (1mg/kg) promoted a significant reduction of spontaneous nociception induced by trypsin in the mouse paw. In contrast, the oral administration of AS605240 did not significantly modify capsaicin-evoked nociception, although this inhibitor was effective when dosed by i.c.v. route. Noteworthy, AS605240 (1mg/kg) was able to prevent c-Fos and phospho-Akt immunopositivity at the spinal cord of trypsin-injected mice, either into the back of the neck or the paws. To conclude, PI3Kγ inhibition might well represent a valuable alternative for treating inflammatory and painful conditions, as well as pruritus.
authors: Postgraduate Program in Medicine and Health Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil School of Pharmacy, PUCRS, Porto Alegre, RS, Brazil Department of Chemistry, Centre of Biological Sciences, Universidade Federal de Santa Caterina (UFSC), Florianópolis, SC, Brazil Department of Pathology, PUCRS, Porto Alegre, RS, Brazil Postgraduate Program in Cellular and Molecular Biology, PUCRS, Porto Alegre, RS, Brazil Institute of Toxicology, PUCRS, Porto Alegre, RS, Brazil School of Dentistry, PUCRS, Porto Alegre, RS, Brazil.
authors: Paula Juliana Seadi
authors: PJS
authors: Pereira
authors: Lais Fernanda
authors: LF
authors: Lazarotto
authors: Paulo César
authors: PC
authors: Leal
authors: Tiago Giuliani
authors: TG
authors: Lopes
authors: Fernanda Bueno
authors: FB
authors: Morrone
authors: Maria Martha
authors: MM
authors: Campos
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D009443:Neuritis / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism* / Q000633:toxicity
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D014357:Trypsin