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 et al., 1992; Kieffer et al., 1992), and the two other receptor genes were cloned by homology (Mestek et al., 1995; Simonin et al., 1994; Simonin et al., 1995). Opioid receptors belong to the superfamily of G-protein coupled receptors (Kieffer, 1995; Trigo et al., 2010), with coupling to Gi/Go proteins (Law et al., 2000), and their structure was solved at high-resolution by X-Ray crystallography (Granier et al., 2012; Manglik et al., 2012; Wu et al., 2012). The opioid system is broadly expressed in the nervous system, particularly within the neurocircuitry of addiction (Koob and Volkow, 2010). Both peptides and receptors are present in areas associated with reward, motivation, learning and stress (Le Merrer et al., 2009; Mansour et al., 1995), and therefore plays a key role in many aspects of addictive behaviors (see (Lutz and Kieffer, 2013).
