Inhibition of phosphatidylinositol-3 kinase γ reduces pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice

• Published in: Pain (Amsterdam) Vol. 152; no. 12; pp. 2861 - 2869
• Main Authors: Pereira, Paula Juliana Seadi, Lazarotto, Lais Fernanda, Leal, Paulo César, Lopes, Tiago Giuliani, Morrone, Fernanda Bueno, Campos, Maria Martha
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier B.V 01.12.2011; Elsevier
• Subjects: Animals; AS605240; Biological and medical sciences; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Fundamental and applied biological sciences. Psychology; General pharmacology; Inflammation - drug therapy; Inflammation - enzymology; Inflammation - metabolism; Injections, Intraventricular; Itch; Male; Medical sciences; Mice; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - enzymology; Neuritis - drug therapy; Neuritis - enzymology; Neuritis - metabolism; Nociception - drug effects; Nociception - physiology; PAR-2; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phosphoinositide-3 Kinase Inhibitors; PI3Kγ; Pruritus - chemically induced; Pruritus - drug therapy; Pruritus - enzymology; Quinoxalines - pharmacology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Thiazolidinediones - pharmacology; Trypsin; Trypsin - metabolism; Trypsin - toxicity; Vertebrates: nervous system and sense organs; PAR-2; AS605240; Itch; Trypsin; Mice; PI3Kγ; Skin disease; Spinal cord; P13Kγ; Capsaicin; Central nervous system; Pruritus; Recruitment; Itching; Behavior; Neck; Tumor necrosis factor α; Nociception; Edema; Cytokine; Rodentia; Oral administration; Vertebrata; Mammalia; Treatment; Mouse; Neutrophil
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2011.09.016

It is suggested that phosphatidylinositol-3 kinase γ activation represents a relevant signaling pathway implicated in the pruriceptive, inflammatory, and nociceptive responses evoked by trypsin in mice. 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 (1 mg/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 (1 mg/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 (1 mg/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.