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Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway.

Muris Humo, Beyza Ayazgök, Léa J. Becker, E. Waltisperger, Tomi Rantamäki, Ipek Yalcin

Progress in Neuro-Psychopharmacology and Biological Psychiatry February 25, 2020 DOI: 10.1016/j.pnpbp.2020.109898 (opens in new tab)

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Study at a glance

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Characteristics Preclinical study Peer reviewed
Population Mice with chronic neuropathic pain
Intervention Ketamine
Dose 15 mg/kg, i.p.
Duration Up to 72 hours after administration
Topics Depression Esketamine Ketamine
Key points A single systemic administration of ketamine transiently alleviated mechanical hypersensitivity but produced a longer-lasting antidepressant effect, and normalized MKP-1 and pERK expression in the anterior cingulate cortex.

Abstract

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms. However, the molecular characteristics of its role in chronic pain-induced depression remain largely unexplored. Hence, we studied the behavioral and molecular effects of a single systemic administration of ketamine (15 mg/kg, i.p.) on mechanical hypersensitivity and depressive-like consequences of chronic neuropathic pain. We showed that ketamine transiently alleviated mechanical hypersensitivity (lasting <24 h), while its antidepressant effect was observed even 72 h after administration. In addition, ketamine normalized the upregulated expression of the mitogen activated protein kinase (MAPK) phosphatase 1 (MKP-1) and the downregulated phosphorylation of extracellular signal-regulated kinase (pERK) in the anterior cingulate cortex (ACC) of mice displaying neuropathic pain-induced depressive-like behaviors. This effect of ketamine on the MKP-1 was first detected 30 min after the ketamine administration and persisted until 72 h. Altogether, these findings provide insights into the behavioral and molecular changes associated with single ketamine administration in the comorbidity of chronic pain and depression.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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