Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.

Abstract

Kappa opioid (KOP) receptor antagonists and delta opioid (DOP) receptor agonists have antidepressant-like effects in animal tests and may be useful for treatment-resistant depression in humans. In this study, we examined whether the combination of a KOP receptor antagonist and a DOP receptor agonist would produce a better than additive effect (i.e. synergy). LY2444296 is a short-acting selective nonpeptide KOP receptor antagonist. ADL5859 is a selective nonpeptide DOP receptor agonist which does not produce seizures and EEG disturbances. Each compound and combinations of the two were examined in the forced swim test (FST) one h post injection, a screening test for antidepressant-like effect, in male adult C57BL/6J mice (Jackson Lab). LY2444296 [subcutaneous (s.c.) injection] at 10 and 30mg/kg, but not 3mg/kg, significantly decreased immobility time in a dose-dependent manner. Intraperitoneal (i.p.) injections of ADL5859 also reduced immobility time dose-dependently at doses of 3 and 10mg/kg, but not at 1mg/kg. An analysis was conducted using the method of Tallarida and Raffa (2010), which employed dose equivalence. The relative potency of the drugs was determined to be LY2444296: ADL5859=1:0.28, which was the dose ratio for combination studies. Six combinations of the two compounds were tested in mice at a fixed dose ratio. We found that LY2444296 and ADL5859 yielded significant synergistic effects for the antidepressant-like effect at the combined dose ranging from 3.84mg/kg to 9.0mg/kg. ADL5859 (10mg/kg), LY2444296 (30mg/kg) and their combined dose (3.84mg/kg) had no effects on locomotor activities. Since the two drugs have distinct pharmacological profiles, such a synergism will allow use of lower doses of both drugs to achieve desired antidepressant effects with fewer side effects.

• Authors: Peng Huang, Julia Tunis, Christopher Parry, Ronald Tallarida, Lee-Yuan Liu-Chen
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 781 Pg. 53-9 (Jun 15 2016) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 27044434 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Antidepressive Agents
• Benzamides
• Benzopyrans
• LY 2444296
• N,N-diethyl-4-(5-hydroxyspiro(chromene-2,4'-piperidine)-4-yl)benzamide
• Receptors, Opioid, delta
• Receptors, Opioid, kappa

Topics

• Animals
• Antidepressive Agents (pharmacology)
• Behavior, Animal (drug effects)
• Benzamides (pharmacology)
• Benzopyrans (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Locomotion (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Opioid, delta (agonists)
• Receptors, Opioid, kappa (antagonists & inhibitors)
• Swimming