Opiates, including morphine, are potent analgesic compounds and represent major therapeutic drugs to treat severe pain. In addition, opiates induce strong euphoria and repeated exposure often leads to dependence and eventually opioid addiction. Milestones in discoveries of the opioid system are shown in Figure 1. Morphine, the most active component of opium, was isolated in 1805 by Serturner. Opioid receptors were described in 1973, based on opioid binding sites referred as mu, delta and kappa (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973). Met- and Leu- enkephalins were characterized in 1975, and altogether three families of endogenous opioid peptides precursors (pre-proenkephalin pEnk, pre-prodynorphin pDyn and proopiomelanocortin POMC) were identified in the late 70’s (Goldstein et al., 1979; Guillemin et al., 1976; Hughes et al., 1975; Li and Chung, 1976). Genes encoding opioid peptide precursors were isolated in the early 80’s (pEnk (Comb et al., 1982; Gubler et al., 1982; Noda et al., 1982); pDyn (Kakidani et al., 1982); POMC (Nakanishi et al., 1979). The first opioid receptor gene, encoding delta receptors, isolated by expression cloning in 1992 (Evans
