Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 11, pp 1393–1400 | Cite as

Antinociceptive and antidepressive efficacies of the combined ineffective doses of S-ketamine and URB597

  • Mohaddeseh Ebrahimi-Ghiri
  • Faezeh Shahini
  • Fatemeh Khakpai
  • Mohammad-Reza ZarrindastEmail author
Original Article


Clinical studies have demonstrated that the NMDA receptor antagonist ketamine produces rapid antidepressant responses. There are safety concerns and adverse effects that limit the utilization of ketamine in psychiatry. Some studies have suggested combination therapy for optimal ketamine use. In this study, we evaluated the potential for combination therapy of ineffective doses of ketamine and fatty acid amide hydrolase inhibitor URB597 for the treatment of depression and pain in male NMRI mice. Intraperitoneal administration of ketamine (10 mg/kg) at the time intervals of 115, 145, and 160 min and ketamine (5 mg/kg) at the time interval of 160 min after administration increased the tail-flick latency, indicating an antinociceptive effect. The same doses of ketamine decreased immobility time in the forced swim test (FST), showing an antidepressant-like effect. Moreover, URB597 at the doses of 0.5 and 1 mg/kg induced an antinociceptive effect, while it at the dose of 1 mg/kg produced an antidepressant-like response. Furthermore, co-administration of the ineffective doses of ketamine (2.5 mg/kg) and URB597 (0.1 mg/kg) caused antinociceptive and antidepressant-like effects, while each one of them alone did not alter the performance of mice in the FST and tail-flick tests. It should be noted that none of the treatments alter animal locomotor activity compared to the control group. Therefore, the combined administration of ineffective doses of ketamine and URB597 might be an effective strategy in the therapy of depression and pain.


Antinociceptive Antidepressant-like effect S-ketamine URB597 Mice 


Authors’ contribution

FS acquired the animal data. ME wrote the manuscript. ME, FK, and MZ were responsible for the study concept, design, and assisted with the data analysis and interpretation of findings. All authors critically reviewed the content and approved the final version for publication.

Compliance with ethical standards

The study was carried out in accordance with ethical standards in all aspects.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mohaddeseh Ebrahimi-Ghiri
    • 1
  • Faezeh Shahini
    • 2
  • Fatemeh Khakpai
    • 3
  • Mohammad-Reza Zarrindast
    • 2
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of Biology, Faculty of SciencesUniversity of ZanjanZanjanIran
  2. 2.Department of Pharmacology, School of MedicineTehran University of Medical SciencesTehranIran
  3. 3.Cognitive and Neuroscience Research Center (CNRC), Tehran Medical SciencesIslamic Azad UniversityTehranIran
  4. 4.Iranian National Center for Addiction StudiesTehran University of Medical SciencesTehranIran
  5. 5.Institute for Cognitive Science Studies (ICSS)TehranIran
  6. 6.Department of Neuroendocrinology, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran

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