Major depressive disorder was shown to be associated with a reduction in response to rewarding stimuli in the dopaminergic mesolimbic pathway in a recent neuroimaging study (Forbes et al, 2009). This neuronal network is modulated by opioids at the level of dopamine (DA) neurons and afferent structures, typically by activation of mu- and delta-opioid receptors (MORs and DORs, respectively) enhancing reward- and motivation-related processes. Therefore, a deficit in endogenous opioids, mainly enkephalins (ENKs), in the nucleus accumbens and ventral tegmental area, may lead to a decrease in the neurobiological control of mood states and reward. To develop fast-acting therapeutics for severe depression, particularly in adolescents, MORs and DORs have been investigated for potential antidepressant activity, using: (i) exogenous agonists and antagonists for both receptors and (ii) ENKs protected from their inactivating enzymes by dual inhibitors such as RB101 (N-(R,S)-2-benzyl-3-((S)(2-amino-4-methyl-thio)-butyldithio)-1-oxopropyl)-1-phenylalanine benzyl ester) (Noble and Roques, 2007), which induced a synaptic enhancement of phasically released ENKs. In animal models, exogenous delta agonists such as SNC80 ((+)-4-(aR)-a-((2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl)-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide induce highly significant antidepressant effects whereas mu agonists do not. This is associated with an increase in brain-derived neurotrophic factor mRNA (Jutkiewicz, 2006), which has been suggested to have a role in antidepressant effects, as well as an indirect increase in DA efflux into the striatum (Bosse et al, 2008). As frequently observed with some delta agonists, SNC80 causes seizures. This is not observed with RB101, which is effective in almost all animal models of depression, eg, decreases conditioned suppression of mobility in mice, immobility in the forced swim test in rats (Jutkiewicz, 2006) and in mice (Nieto et al, 2005) and escape failures in the learned helplessness test (Noble and Roques, 2007). The effects of RB101 are observed after a single administration and no tolerance is observed during chronic use (Cordonnier et al, 2005). Moreover, stimulation of opioid receptors by RB101 protected ENKs does not induce the undesirable side effects of morphine (Noble and Roques, 2007). The selective DOR antagonist naltrindole or DA antagonists reverse antidepressant effects of RB101 and SNC80, demonstrating that the effects are mediated by DORs, and involve the DA-dependent mesolimbic pathway. Consistently, DOR KO mice present depressive-like behaviors, which are reversed by antidepressant drugs, whereas MOR KO mice are unaffected (Filliol et al, 2000; Nieto et al, 2005). The key role of interconnected endogenous opioid and DAergic systems in mood control is demonstrated by the facilitation of antidepressant-like effects of RB101 after deafferentation of the DAergic mesolimbic pathway (Cordonnier et al, 2005), which increases the concentrations of PENK and ENKs. Taken together, these results suggest a phasic control of the DAergic mesolimbic pathway by ENKs, which may be impaired in depressive-like syndromes, and clinical studies are starting to investigate this endogenous opioid-DA interaction in human depression (Kennedy et al, 2006; Scott et al, 2008). The development of (i) dual orally active ENK inhibitors with strong analgesic properties and immediate antidepressant effects (Noble and Roques, 2007) and (ii) delta agonists devoid of side effects may lead to significant improvements in the treatment of depression and mood disorders.

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