title: Antinociceptive and Anti-Inflammatory Effects of Ketamine and the Relationship to Its Antidepressant Action and GSK3 Inhibition.
abstract: Ketamine (KET), a NMDA antagonist, exerts an antidepressant effect at subanaesthetic doses and possesses analgesic and anti-inflammatory activities. We evaluated the involvement of KET antinociceptive and anti-inflammatory effects with its antidepressant action. Male Swiss mice were subjected to formalin, carrageenan-induced paw oedema and forced swimming tests, for assessing antinociceptive, anti-inflammatory and antidepressant effects. The treatment groups were as follows: control, KET (2, 5 and 10 mg/kg), lithium (LI: 5 mg/kg) and KET2 + LI5 combination. Immunohistochemistry analyses (TNF-α, iNOS, COX-2 and GSK3) in oedematous paws were performed. KET5 and KET10 reduced licking times in neurogenic (22 and 38%) and inflammatory (67 and 78%) phases of the formalin test, respectively, as related to controls. While LI5 inhibited the second phase by 24%, the licking time was inhibited by 26 and 59% in the KET2 + LI5 group (first and second phases). Furthermore, oedema volumes were reduced by 37 and 45% in the KET5 and KET10 groups, respectively. Oedema reductions were 29% in the LI5 group and 48% in the KET2 + LI5 group. In the forced swimming test, there were 23, 38 and 53% decreases in the immobility time in KET2, KET5 and KET10 groups, respectively. While LI5 caused no significant effect, decreases of 52% were observed with KET2 + LI5. KET also decreased TNF-α, iNOS, COX-2 and GSK3 immunostainings in oedematous paws, effects intensified with KET2 + LI5. We showed that KET presents antinociceptive and anti-inflammatory effects associated with its antidepressant response. Furthermore, our results indicate the close involvement of GSK3 inhibition and blockade of inflammatory responses, in the antidepressant drug effect.
authors.affiliation: Faculty of Medicine, Estácio of Juazeiro do Norte (FMJ), Juazeiro do Norte, Ceará, Brazil.
authors.forename: Eduardo Mulato
authors.initials: EM
authors.lastname: do Vale
authors.affiliation: Faculty of Medicine, Estácio of Juazeiro do Norte (FMJ), Juazeiro do Norte, Ceará, Brazil.
authors.forename: Cecília Coelho
authors.initials: CC
authors.lastname: Xavier
authors.affiliation: Faculty of Medicine, Estácio of Juazeiro do Norte (FMJ), Juazeiro do Norte, Ceará, Brazil.
authors.forename: Brenda Gomes
authors.initials: BG
authors.lastname: Nogueira
authors.affiliation: Faculty of Medicine, Estácio of Juazeiro do Norte (FMJ), Juazeiro do Norte, Ceará, Brazil.
authors.forename: Bruna Caldas
authors.initials: BC
authors.lastname: Campos
authors.affiliation: Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Pedro Everson Alexandre
authors.initials: PE
authors.lastname: de Aquino
authors.affiliation: Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Roberta Oliveira
authors.initials: RO
authors.lastname: da Costa
authors.affiliation: Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Luzia Kalyne Almeida Moreira
authors.initials: LK
authors.lastname: Leal
authors.affiliation: Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Silvânia Maria Mendes
authors.initials: SM
authors.lastname: de Vasconcelos
authors.affiliation: Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Kelly Rose Tavares
authors.initials: KR
authors.lastname: Neves
authors.affiliation: Faculty of Medicine, Estácio of Juazeiro do Norte (FMJ), Juazeiro do Norte, Ceará, Brazil.|Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil.
authors.forename: Glauce Socorro
authors.initials: GS
authors.lastname: de Barros Viana
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D003863:Depression / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007150:Immunohistochemistry; D007649:Ketamine / Q000008:administration & dosage / Q000627:therapeutic use*; D008094:Lithium / Q000627:therapeutic use; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D007649:Ketamine; D008094:Lithium; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse