Review
Functional relevance of μ–δ opioid receptor heteromerization: A Role in novel signaling and implications for the treatment of addiction disorders: From a symposium on new concepts in mu-opioid pharmacology

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Abstract

Morphine and other opiates are among the most widely prescribed and clinically useful medications for the treatment of chronic pain. However, the applicability of these compounds has been severely hampered by the rapid development of tolerance and physical dependence that typically accompanies their repeated use. A growing body of evidence has implicated the regulated functioning of μ–δ opioid receptor heteromers in both the modulation of morphine-mediated antinociception, and in the limitation of undesirable side effects resulting from chronic opiate exposure. Moreover, μ–δ heteromers exhibit unique ligand binding characteristics and signaling properties, indicating that pharmacological targeting of the μ–δ heteromer may represent a novel therapeutic approach for the management of chronic pain and addiction disorders. Therefore, the present review will attempt to summarize the latest relevant findings regarding the regulation and functional characteristics of the μ–δ heteromer both in vitro and in vivo.

Introduction

G-protein coupled receptors (GPCRs), also referred to as seven-transmembrane receptors, are a large family of cell surface proteins that have been implicated in almost all physiological processes. This is accomplished by their ability to bind a diverse array of molecules, and then convert these surface stimuli into intracellular signaling cascades via their binding of heterotrimeric guanosine proteins (G proteins; Rozenfeld and Devi, 2011). Previously, it was believed that these receptors functioned only in their monomeric form, with each GPCR being associated with a distinct G-protein-mediated signaling cascade. Recent evidence from converging methodologies suggests that GPCRs can heterodimerize under both normal and pathophysiological conditions. While the existence of such heterodimers is still being actively debated (Vilardaga et al., 2009, Kenakin et al., 2010), accumulating evidence demonstrates that many GPCRs have the ability to form functional dimers, oligomers, and even heteromers. Many have suggested that such heteromerization may represent a common mechanism by which GPCR activity and signaling may be modulated (Devi, 2001, Angers et al., 2002, George et al., 2002, Prinster et al., 2005, Milligan, 2007). While numerous examples of functional GPCR heteromers have been documented in recent years (Prinster et al., 2005, Milligan, 2007), heteromers composed of opioid receptors have garnered particular interest as novel therapeutic targets for the modulation of antinociception, as well as their role in tolerance and addiction to opiate compounds.

The three presently known opioid receptors, μ, δ, and κ, are all members of the family A GPCRs, and as such exhibit many of the same functional characteristics as other family A receptors. All three opioid receptors are coupled to Gi/o proteins, inhibit adenylyl cyclase and cAMP activity in vivo, and are functionally sensitive to pertussis toxin (Cox, 2010). As with other members of this class of receptors, the opioid receptors have been shown to undergo both homo- and heterotypic interactions in heterologous cell lines (Jordan and Devi, 1999, George et al., 2000, Gomes et al., 2000). The results of such studies have revealed the existence of opioid receptor heteromers possessing unique ligand binding characteristics and signaling properties that are distinct from those identified for the individual constituents of the heteromer in question (Rios et al., 2001, Gomes et al., 2003, Gomes et al., 2004). Of particular clinical relevance, however, are heteromers composed of the μ and δ opioid receptors. Work from our laboratory and others have provided substantial evidence for the existence of opioid receptor heteromers using a variety of direct and indirect methods. As will be addressed in the present review, μ–δ heteromers are now known to modulate μ-agonized antinociception, in addition to significantly modulating the development of tolerance to the antinociceptive effects of opiate compounds. Importantly, modulating the functional characteristics of these receptor heteromers may represent a novel therapeutic target for the management of chronic pain as well as opiate addiction disorders (Rozenfeld and Devi, 2007). Consequently, this review will attempt to summarize what is presently known about the μ–δ heteromer, in addition to the latest emerging ideas implicating the μ–δ heteromer as a novel target for the treatment of chronic pain and addiction disorders.

Section snippets

Pharmacology and the μ–δ receptor

Pharmacological tools provided some of the earliest evidence supporting the existence of heteromers of the μ and δ receptors, when it was observed that endogenous δ-selective ligands, such as Leu-enkephalin, and exogenous synthetic analogues of Leu-enkephalin (FK33824) had the ability to synergistically enhance low levels of morphine-mediated analgesia in a dose dependent manner in vivo (Lee et al., 1980). Subsequent to these initial findings, additional research observed that pretreatment with

Direct evidence of μ–δ receptor heteromers

With their established role in the development of analgesic tolerance, and interest peaking in the μ–δ heteromer as a potential therapeutic target for the management of chronic and/or neuropathic pain, it is of great interest to chart the localization of these heteromers across the neuroaxis. To facilitate such studies, using a subtractive immunization strategy, we generated monoclonal antibodies that selectively recognize the μ–δ heteromer in order to directly detect its regulation and

Conclusions

To date, heteromers of the μ and δ receptors have been found in vivo through the use of monoclonal antibodies, where their expression has been shown to be upregulated by chronic morphine exposure (Cahill et al., 2001, Morinville et al., 2003, Abul-Husn et al., 2007, Gupta et al., 2010). Moreover, these heteromers are not only upregulated by morphine, but modulation of their functioning appears to play a critical role in the development of antinociceptive tolerance and in opiate dependence (

Role of funding source

This study was partly supported by funds from NIH grants DA 008863 and DA 019521 (to L.A.D.).

Contributors

S.D.S. conducted literature research and wrote the manuscript; L.A.D. provided mentorship and guidance in its preparation and helped write the manuscript. All authors contributed to and have approved the final manuscript prior to submission.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

We thank Drs. R. Rozenfeld and I. Gomes for critical reading of this manuscript and for helpful suggestions in the preparation of the final manuscript.

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    This paper was presented in a symposium at the Behavior, Biology, and Chemistry: Translational Research in Addiction meeting on March 5, 2011 in San Antonio, TX, entitled “New concepts in mu-opioid pharmacology-implications for addiction and its management”.

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