Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways.

Human opiorphin protects enkephalins from degradation by human neutral endopeptidase and aminopeptidase-N and inhibits pain perception in various behavioral rodent models of pain via endogenous enkephalin-related activation of opioidergic pathways. In addition to pain control, endogenous opioid pathways are also implicated in the modulation of emotion-related behaviors. Thus, we explored the dose-dependent motivational responses induced by opiorphin using the forced swim test, the standard rat model of depression. In addition, to further understand the endogenous events triggered by opiorphin, we investigated the specific involvement of mu- or delta-opioid receptor-dependent pathways. In parallel, the locomotor activity test was used to detect possible sedation or hyperactivity. Here, we report for the first time that at 1-2 mg/kg i.v. doses, opiorphin elicited antidepressant-like effects by activating endogenous delta-opioidergic pathways, since that activation was reversed by the selective delta-opioid antagonist naldrindole (10 mg/kg i.p.). The antidepressive behavioral responses exerted by opiorphin are specific at systemically active doses. Treated-rats did not develop either hypo- or hyper-active responses in a locomotor test or amnesic behavioral response in the passive avoidance rat model. In addition, opiorphin did not induce either anxiolytic-, or anxiogenic-like responses in the conditioned defensive burying test. Taking the data together, we conclude that opiorphin is able to elicit antidepressant-like effects, mediated via delta-opioid receptor-dependent pathways, by modulating the concentrations of endogenous enkephalin released in response to specific physical and/or psychological stimuli. Thus, opiorphin or optimized derivatives is a promising single candidate to treat disorders that include both pain and mood disorders, particularly depression.