Antinociceptive and Anti‐Inflammatory Effects of Ketamine and the Relationship to Its Antidepressant Action and GSK3 Inhibition

• Published in: Basic & clinical pharmacology & toxicology 2016-12, Vol.119 (6), p.562-573
• Main Authors: Vale, Eduardo Mulato, Xavier, Cecília Coelho, Nogueira, Brenda Gomes, Campos, Bruna Caldas, Aquino, Pedro Everson Alexandre, Costa, Roberta Oliveira, Leal, Luzia Kalyne Almeida Moreira, Vasconcelos, Silvânia Maria Mendes, Neves, Kelly Rose Tavares, Barros Viana, Glauce Socorro
• Format: Article
• Language: English
• Subjects: Analgesics - administration & dosage; Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antidepressive Agents - administration & dosage; Antidepressive Agents - therapeutic use; Behavior, Animal - drug effects; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Depression - metabolism; Depression - pathology; Depression - prevention & control; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Edema; Excitatory Amino Acid Antagonists - administration & dosage; Excitatory Amino Acid Antagonists - therapeutic use; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Immunohistochemistry; Ketamine - administration & dosage; Ketamine - therapeutic use; Lithium - therapeutic use; Male; Mice; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - therapeutic use; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Subcutaneous Tissue - drug effects; Subcutaneous Tissue - metabolism; Subcutaneous Tissue - pathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.12637

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.