Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects

Abstract

Nonpeptidic delta-opioid receptor agonists produce antidepressant-like effects in rodents, and compounds that inhibit the breakdown of endogenous opioid peptides have antidepressant-like effects in animal models. In this study, the behavioral effects of the enkephalinase inhibitor, RB101 (N-[(R, S)-2-benzyl-3-[(S)(2-amino-4-methyl-thio)-butyldithio]-1-oxopropyl]-l-phenylalaninebenzyl ester), were examined. Specifically, the effects of RB101 on convulsive activity, locomotor activity, and antidepressant-like effects in the forced swim test were studied in Sprague-Dawley rats, and the opioid receptor types mediating these effects were examined by antagonist studies. In addition, the effects of RB101 on brain-derived neurotrophic factor (BDNF) mRNA expression were evaluated in relation to its antidepressant effects. RB101 produced delta-opioid receptor-mediated antidepressant effects (32 mg/kg i.v. and 100 mg/kg i.p.) and increased locomotor activity (32 mg/ kg i.v.) in rats. RB101 did not produce convulsions or seizures and did not alter BDNF mRNA expression. In conclusion, RB101 has the potential to produce antidepressant effects without convulsions.

Use of preproenkephalin knockout mice and selective inhibitors of enkephalinases to investigate the role of enkephalins in various behaviours

“…One possible explanation could originate from the reported specific up-regulation of delta receptors in limbic structures of Penk1−/− mice (Clarke et al 2003b). This hypothesis is in agreement with previous studies, showing clearly that the antidepressant-like effects observed after RB101 administration were related to stimulation of delta opioid receptors by the endogenous enkephalins protected from their enzymatic degradation (Baamonde et al 1992;Jutkiewicz et al 2006;Nieto et al 2005). Moreover, in a recent study, we have already demonstrated that the residual antidepressant-like effect of RB 101 in Penk1−/− mice was blocked by the delta opioid selective antagonist, naltrindole (Bilkei-Gorzo et al 2007).…”

“…The dual inhibitors of enkephalin catabolism have been previously reported to elicit antidepressant-like effects in several animal models (Baamonde et al 1992;Jutkiewicz et al 2006;Nieto et al 2005;Tejedor-Real et al 1998). As expected, in the forced swim test, RB101 induced a highly significant decrease in the immobility time in wild-type mice, whereas a slight and plateauing reduction in immobility time was observed for the highest doses of the dual inhibitor in Penk1−/− animals (Fig.…”

In Vitro and In Vivo Metabolism of a Selective δ-Opioid Receptor

“…In several studies, the opioid receptors were proposed as a novel target system for the treatment of depression and anxiety (Nieto et al, 2005;Jutkiewicz et al, 2006;Saitoh et al, 2008). Opioid receptors are a family of G protein-coupled receptors and are classified as ␦, , and receptors, according to the endogenous opioid peptides, namely the endorphins, enkephalins, and dynorphin, respectively (Raynor et al, 1994).…”

Potentiation of the control of pain by endogenous enkephalins through inhibition of their enzymatic inactivation, a new approach towards physiological analgesics

“…La raison a été discutée plus haut, et les références aux expériences qui le démontrent peuvent être trouvées dans différentes revues [13,17,19]. De même, l'effet antidépres-seur qui joue probablement sur la composante émotionnelle de la douleur trouve sa justification dans l'activation centrale des récepteurs delta [1,7]. L'absence de tolérance par rapport à la morphine est due à la différence dans le trafic des récepteurs stimulés par les enképhalines ou la morphine.…”