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Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.
Eur J Pharmacol. 2016 Jun 15; 781:53-9.EJ

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+Show Affiliations

Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States.Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, United States. Electronic address: lliuche@temple.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27044434

Citation

Huang, Peng, et al. "Synergistic Antidepressant-like Effects Between a Kappa Opioid Antagonist (LY2444296) and a Delta Opioid Agonist (ADL5859) in the Mouse Forced Swim Test." European Journal of Pharmacology, vol. 781, 2016, pp. 53-9.
Huang P, Tunis J, Parry C, et al. Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test. Eur J Pharmacol. 2016;781:53-9.
Huang, P., Tunis, J., Parry, C., Tallarida, R., & Liu-Chen, L. Y. (2016). Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test. European Journal of Pharmacology, 781, 53-9. https://doi.org/10.1016/j.ejphar.2016.03.061
Huang P, et al. Synergistic Antidepressant-like Effects Between a Kappa Opioid Antagonist (LY2444296) and a Delta Opioid Agonist (ADL5859) in the Mouse Forced Swim Test. Eur J Pharmacol. 2016 Jun 15;781:53-9. PubMed PMID: 27044434.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test. AU - Huang,Peng, AU - Tunis,Julia, AU - Parry,Christopher, AU - Tallarida,Ronald, AU - Liu-Chen,Lee-Yuan, Y1 - 2016/04/01/ PY - 2015/12/16/received PY - 2016/03/29/revised PY - 2016/03/31/accepted PY - 2016/4/6/entrez PY - 2016/4/6/pubmed PY - 2017/3/9/medline KW - Antidepressant KW - Delta opioid agonist KW - Forced swim test KW - Kappa opioid antagonist KW - Synergy SP - 53 EP - 9 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 781 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/27044434/Synergistic_antidepressant_like_effects_between_a_kappa_opioid_antagonist__LY2444296__and_a_delta_opioid_agonist__ADL5859__in_the_mouse_forced_swim_test_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(16)30201-1 DB - PRIME DP - Unbound Medicine ER -