ABSTRACT
The delta receptor was the first opioid receptor to be cloned in 1992, almost 20 years after opioid binding sites were discovered in the brain [1,2]. Cloning was achieved simultaneously by two independent teams, using an expression strategy [3,4]. Homology cloning techniques then delivered the whole opioid
receptor gene family. Gene encoding the previously proposed mu, delta and kappa receptors were isolated in several species, as well as the nonopioid homologous ORL-1 receptor [reviewed in 5]. The next experiments used receptor domain swapping, truncation, and site-directed mutagenesis to elucidate structure-activity relationships of opioid receptors at the cellular level. To date, receptor mutagenesis has provided a fairly clear view of the opioid binding site, as well as some clues on possible signaling and regulatory determinants, although the general picture of delta receptor activation is still missing. Genetic studies were initiated and mice lacking functional opioid receptor genes were created and studied behaviorally. Gene knockout in mice has brought unexpected and novel findings on delta receptor function in vivo, that should promote the search for novel delta ligands and therapeutic areas. Together, molecular approaches have uniquely addressed receptor function both at the membrane and in the complex environment of neural circuits. In this chapter we will briefly summarize some important findings that have stemmed from receptor in vitro and in vivo mutagenesis and told us how delta receptors operate at the protein level as well as within the brain.
