title: GRPR/PI3Kγ: Partners in Central Transmission of Itch.
abstract: The gastrin-releasing peptide (GRP) and its receptor (GRPR) are important components of itch transmission. Upstream, but not downstream, aspects of GRPR signaling have been investigated extensively. We hypothesize that GRPR signals in part through the PI3Kγ/Akt pathway. We used pharmacological, electrophysiological, and behavioral approaches to further evaluate GRPR downstream signaling pathways. Our data show that GRP directly activates small-size capsaicin-sensitive DRG neurons, an effect that translates into transient calcium flux and membrane depolarization (∼ 20 mV). GRPR activation also induces Akt phosphorylation, a proxy for PI3Kγ activity, in ex vivo naive mouse spinal cords and in GRPR transiently expressing HEK293 cells. The intrathecal injection of GRP led to intense scratching, an effect largely reduced by either GRPR antagonists or PI3Kγ inhibitor. Scratching behavior was also induced by the intrathecal injection of an Akt activator. In a dry skin model of itch, we show that GRPR blockade or PI3Kγ inhibition reversed the scratching behavior. Altogether, these findings are highly suggestive that GRPR is expressed by the central terminals of DRG nociceptive afferents, which transmit itch via the PI3Kγ/Akt pathway.
  
  
  CONCLUSIONS
  Itch is the most common symptom of the skin and is related to noncutaneous diseases. It severely impairs patients' quality of life when it becomes chronic and there is no specific or effective available therapy, mainly because itch pathophysiology is not completely elucidated. Our findings indicate that the enzyme PI3Kγ is a key central mediator of itch transmission. Therefore, we suggest PI3Kγ as an attractive target for the development of new anti-pruritic drugs. With this study, we take a step forward in our understanding of the mechanisms underlying the central transmission of itch sensation.
authors.affiliation: Programa de Pós-graduação em Biologia Celular e Molecular, Instituto de Toxicologia e Farmacologia, Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and.
authors.forename: Paula J S
authors.initials: PJ
authors.lastname: Pereira
authors.affiliation: Faculdade de Medicina e Ciências da Saúde, Instituto de Toxicologia e Farmacologia.
authors.forename: Gustavo D B
authors.initials: GD
authors.lastname: Machado
authors.affiliation: Faculdade de Medicina e Ciências da Saúde, Instituto de Toxicologia e Farmacologia.
authors.forename: Giuliano M
authors.initials: GM
authors.lastname: Danesi
authors.affiliation: Faculdade de Medicina e Ciências da Saúde, Instituto de Toxicologia e Farmacologia.
authors.forename: Francesca F
authors.initials: FF
authors.lastname: Canevese
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and.
authors.forename: Vemuri B
authors.initials: VB
authors.lastname: Reddy
authors.affiliation: Programa de Pós-graduação em Medicina e Ciências da Saúde, and.
authors.forename: Talita C B
authors.initials: TC
authors.lastname: Pereira
authors.affiliation: Programa de Pós-graduação em Biologia Celular e Molecular, Instituto de Toxicologia e Farmacologia.
authors.forename: Maurício R
authors.initials: MR
authors.lastname: Bogo
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115.
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115.
authors.forename: Cedric
authors.initials: C
authors.lastname: Laedermann
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts 02115.
authors.forename: Sébastien
authors.identifier: http://orcid.org/0000-0001-9932-7174
authors.initials: S
authors.lastname: Talbot
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and maria.campos@pucrs.br camposmmartha@yahoo.com elerner@partners.org.
authors.forename: Ethan A
authors.identifier: http://orcid.org/0000-0001-5480-4133
authors.initials: EA
authors.lastname: Lerner
authors.affiliation: Instituto de Toxicologia e Farmacologia, Programa de Pós-graduação em Medicina e Ciências da Saúde, and Faculdade de Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900, Porto Alegre, RS, Brazil, maria.campos@pucrs.br camposmmartha@yahoo.com elerner@partners.org.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Campos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D001839:Bombesin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002211:Capsaicin / Q000633:toxicity; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D019886:Gastrin-Releasing Peptide / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011537:Pruritus / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D011810:Quinoxalines / Q000494:pharmacology; D011930:Reaction Time / Q000502:physiology; D018004:Receptors, Bombesin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000633:toxicity
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D010446:Peptide Fragments; D011810:Quinoxalines; D018004:Receptors, Bombesin; D045162:Thiazolidinediones; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D003189:p-Methoxy-N-methylphenethylamine; D019886:Gastrin-Releasing Peptide; D058539:Phosphatidylinositol 3-Kinase; C116774:PD 176252; D001839:Bombesin; D002211:Capsaicin
keywords: AS605240; GRPR; PI3Kγ; dry skin; itch; spinal cord