Deletion of the δ Opioid Receptor Gene Impairs Place Conditioning But Preserves Morphine Reinforcement

Background: Converging experimental data indicate that delta opioid receptors contribute to mediate drug reinforcement processes. Whether their contribution reflects a role in the modulation of drug reward or an implication in conditioned learning, however, has not been explored. In the present study, we investigated the impact of delta receptor gene knockout on reinforced conditioned learning under several experimental paradigms. Methods: We assessed the ability of delta receptor knockout mice to form drug-context associations with either morphine (appetitive)- or lithium (aversive)- induced Pavlovian place conditioning. We also examined the efficiency of morphine to serve as a positive reinforcer in these mice and their motivation to gain drug injections, with operant intravenous self-administration under fixed and progressive ratio schedules and at two different doses. Results: Mutant mice showed impaired place conditioning in both appetitive and aversive conditions, indicating disrupted context-drug association. In contrast, mutant animals displayed intact acquisition of morphine self-administration and reached breaking-points comparable to control subjects. Thus, reinforcing effects of morphine and motivation to obtain the drug were maintained. Conclusion: Collectively, the data suggest that delta receptor activity is not involved in morphine reinforcement but facilitates place conditioning. This study reveals a novel aspect of delta opioid receptor function in addiction-related behaviors.