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 30 mg/kg, but not 3 mg/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 10 mg/kg, but not at 1 mg/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 3.84 mg/kg to 9.0 mg/kg. ADL5859 (10 mg/kg), LY2444296 (30 mg/kg) and their combined dose (3.84 mg/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.

“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

“…Previous studies showed a reduced latency to immobility and increased open arm exploration induced by long-acting KOPr antagonists, in cocaine naïve rats (Knoll et al 2007; Mague et al 2003; Pliakas et al 2001). In line with our results, two recent studies reported that systemic administration of norBNI, but not 3 mg/kg LY2444296, reduced anxiety-like and depressive-like behaviors in cocaine naïve mice (Huang et al 2016a; Huang et al 2016b). Long-acting KOPr antagonists have complex pharmacokinetics and pharmacodynamic properties.…”

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

“…Therefore, the effects of these rapid-acting k-antagonists on immobility in the FST are not due to a simple confound with locomotor function. The rapid effects of compounds from this chemical template in the FST (and of LY2444296) have been observed before (Rorick-Kehn et al, 2014;Huang et al, 2016a). This is the first such examination for LY2795050, to our knowledge.…”

Peptides: Production, bioactivity, functionality, and applications

“…This is very imperative because as opioid agonists, they induce an analgesic effect, which is characteristically found in opioid ligands, whereas as opioid antagonists at the NK1 receptors, they block the signals induced by the pronociceptive peptides involved in pain signaling . Furthermore, Huang et al (2016) mentioned that the dynorphin/k opioid (KOP) receptor system leads to adverse emotional conditions. When activated by selective agonists, the receptor system causes strong emotional consequences in humans and conditioned place aversion in animals .…”