In vivo opioid receptor heteromerization: where do we stand?

Abstract

to correct some mis-citations in text and tables, these are marked by an asterisk.Opioid receptors are highly homologous GPCRs that modulate brain function at all levels of neural integration, including autonomous, sensory, emotional and cognitive processing. Opioid receptors functionally interact in vivo, but the underlying mechanisms involving direct receptor-receptor interactions, affecting signalling pathways or engaging different neuronal circuits, remain unsolved. Heteromer formation through direct physical interaction between two opioid receptors or between an opioid receptor and a non-opioid one has been postulated and can be characterized by specific ligand binding, receptor signalling and trafficking properties. However, despite numerous studies in heterologous systems, evidence for physical proximity in vivo is only available for a limited number of opioid heteromers, and their physiopathological implication remains largely unknown mostly due to the lack of appropriate tools. Nonetheless, data collected so far using endogenous receptors point to a crucial role for opioid heteromers as a molecular entity that could underlie human pathologies such as alcoholism, acute or chronic pain as well as psychiatric disorders. Opioid heteromers therefore stand as new therapeutic targets for the drug discovery field. ]enkephalin; DRG, dorsal root ganglion; GNTI, guanidinonaltrindole; GRP, gastrin-releasing peptide; HIV, human immunodeficiency virus; IHC, immunohistochemistry; ISH, in situ hybridization; i.t., intrathecal; KDOP, κ opioid receptor δ opioid receptor agonist antagonist; KOP, κ opioid receptor; MDAN, μ opioid receptor δ opioid receptor agonist antagonist; MOP, μ opioid receptor; NNTA, N-naphthoyl-β-naltrexamine; norBNI, nor-binaltorphimine; pbFRET, photobleaching FRET; TAT, transactivating transcriptional activator LINKED ARTICLESThis The opioid systemThe opioid system is composed of three families of endogenous peptides, the enkephalins, dynorphins and β-endorphin, and three homologous GPCRs, the μ opioid receptor (MOP), δ opioid receptor (DOP) and κ opioid receptor (KOP) (Filizola and Devi, 2013;Cox et al., 2015; receptor nomenclature follows Alexander et al., 2013a). Opioid receptors and endogenous opioid peptides are expressed throughout the nervous system (Le Merrer et al., 2009). The opioid system plays a key role in reward and motivation, and regulates emotional responses and cognition. The system also modulates nociception, neuroendocrine physiology and autonomic functions (see Walwyn et al., 2010;Feng et al., 2012). The involvement of the three opioid receptors in pain control, drug abuse and mood disorders has been extensively studied and has been the focus of recent reviews (Bruchas et al., 2010;Gaveriaux-Ruff and Kieffer, 2011;Pradhan et al., 2011;Raehal et al., 2011;Lutz and Kieffer, 2012;Nadal et al., 2013;Charbogne et al., 2014).Several decades of opioid pharmacology have uncovered the complexity of the opioid system physiology. In particular, the analysis of the effects of opioid drugs ...

Selective and Wash‐Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single‐Molecule Imaging of μ‐Opioid Receptor Dimerization

“…Interestingly, in the above studies μ‐ORs were found to crystallize as dimers . Largely based on previous experiments applying resonance energy transfer methods, these findings support the hypothesis that μ‐ORs might form homodimers . However, the nanoscale organization and dynamics of μ‐ORs on the surface of living cells remain largely unknown, mostly due to technical limitations of conventional methods.…”

“…Opioid receptors (ORs) belong to the family A of rhodopsin‐like G protein‐coupled receptors and occur in three major subtypes, μ, δ and κ . They are predominantly found in the central and peripheral nervous system, where they modulate transmission and perception of pain.…”

“…Because of their importance as drug targets, μ‐ORs have been intensively investigated both, in vitro and in vivo . A major breakthrough in the field has been the determination of high‐resolution three‐dimensional structures of the μ‐OR in complex with an antagonist and, later on, with an agonist and G protein mimetic nanobodies, as well as most recently by cryo‐electron microscopy .…”

Heterologous Regulation of Mu-Opioid (MOP) Receptor Mobility in the Membrane of SH-SY5Y Cells

“…The cellular and pharmacological activities of the MOP receptor are modulated by other GPCR systems (2)(3)(4)(5). In some case, such heterologous regulation involves receptor heteromerization (6), which is considered to confer new binding and endocytosis properties to the complex and/or to promote novel signaling pathways or, conversely, to impair signal transduction (7,8). The heteromerization of the MOP receptor with other opioid receptors, DOP, KOP, and NOP (9 -12) or with non-opioid receptors such as ␣ 2 -adrenergic (13)(14)(15), somatostatin SST 2A (16) or substance P NK1 (17) receptors has been reported.…”

In vivo neuronal co-expression of mu and delta opioid receptors uncovers new therapeutic perspectives

“…Such heteromers would represent the molecular determinant that underlies the integrated changes observed at system level. However, mu-delta in vivo co-expression and heteromerization remain extremely difficult to tackle with existing tools [11] . In vivo co-localization has indeed only been reported in dorsal root ganglia (DRG) [12–14] , spinal cord [15] and within a limited number of brain areas [16–18] but, as for most GPCRs, we still miss in-depth anatomical mapping of opioid receptors in the brain that also provides subcellular resolution.…”