Despite decades of active investigation, relatively basic questions about opioid receptors remain unanswered. The distinct pharmacologic profiles of the various opioid receptors are fairly well-characterized; their molecular basis, including whether they are homomeric or heteromeric, remains unclear (van Rijn & Whistler 2009). For example, researchers have variously proposed that the DOR1 is actually a heterodimer composed of DOR and either MOR (van Rijn & Whistler 2009) or KOR (Bhushan et al. 2004) subunits. Similarly, a provocative report (Yekkirala, Kalyuzhny, & Portoghese 2010) found that the affinity of opiate agonists at MOR-DOR heteromers exceeded that at MOR homomers. DORS are primarily intracellular; chronic opioid use results in substantial translocation to cell membranes where they may form heteromers with MORs (von Zastrow 2010). Increased levels of MOR-DOR heteromers have been reported (Gupta A et al. 2010) after chronic morphine administration. The formation of these MOR-DOR heteromers has recently been implicated (He SQ et al. 2011) as playing a major role in opioid tolerance. DOR antagonists have been shown to block the sensitization to the conditioned rewarding effects of morphine that occurs with
