BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders.

This work was supported by the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, and Université de Strasbourg; the Fondation pour la Recherche Médicale (Grant No. FRM FDT20120925269), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010, and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658); the Spanish Instituto de Salud Carlos III (Red de Trastornos Adictivos, Grant No. RD06/001/001), the Spanish Ministerio de Ciencia e Innovación (No. Ministerio de Ciencia e Innovación [Grant No. SAF2011-29864]), the Catalan Government (Grant No. SGR2009-00131), and Institucio Catalana de Recerca i Estudis Avançats Academia-2008; and NeuroPain (Framework programme 7, European Union)