Involvement of δ-opioid receptors in the effects induced by endogenous enkephalins on learned helplessness model

Abstract

Pharmacological, neurochemical and behavioural findings support a possible role of endogenous opioids in clinical depression. There is evidence from animal studies that δ-opioid receptors are involved in several behavioural responses to opioids, including motivational activities. In the present study, the mixed enkephalin catabolism inhibitor, RB 101 ( N( R, S)-2-benzyl-3[( S)-(2-amino-4-methylthiobutyldithio]-1-oxopropyl)- l-phenylalanine benzyl ester) (1.25, 2.5 and 5 mg/kg), induced a dose-dependent antidepressant-like effect in a learned helplessness model. Thus, RB 101 reversed escape deficits in rats previously subjected to inescapable shocks, suggesting the involvement of endogenous enkephalins in depression. Similar effects were observed after administration of the selective δ-opioid receptor agonist, BUBU (Tyr-D.Ser-( O- tert-butyl)-Gly-Phe-Leu-Thr(O-Tet-butyl-OH)) (1 and 2 mg/kg). Moreover, RB 101 effects were antagonized by administration of naltrindole (NTI) (0.1 mg/kg), which points to a preferential involvement of δ-opioid receptors in this enkephalin-controlled behaviour. As RB 101 has been reported to be almost devoid of opiate-related side-effects, it could represent a promising alternative in the treatment of depressive patients who are unresponsive to, or intolerant of, classical antidepressants.