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[micro]-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose.sup.1-3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown.sup.4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward. Studies in mice show that [micro]-opioid peptide receptor regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection and requires enkephalin-producing neurons., Author(s): Daniel C. Castro [sup.1] [sup.2] [sup.3] [sup.4] , Corinna S. Oswell [sup.1] [sup.4] , Eric T. Zhang [sup.4] [sup.5] , Christian E. Pedersen [sup.4] [sup.5] , Sean C. Piantadosi [...]

μ-Opioid receptors (pORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of [...]

Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor., The three classical opioid receptors (μ, κ and δ-OR) and the related nociceptin/orphanin FQ peptide receptor (NOP) are G-protein-coupled receptors (GPCRs) essential for regulating nociception, mood and awareness (1). These [...]

The opioid receptor family comprises three members, the μ-, δ- and κ-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-proteincoupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-opioid receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood (1). The structures of the μ-OR and κ-OR have recently been solved (2,3). Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the μ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the 'message-address' model of opioid receptor pharmacology (4,5), in which distinct 'message' (efficacy) and 'address' (selectivity) determinants are contained within a single ligand. Comparison of the address region of the o-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well., Opioid receptors have an important role in the central nervous system, regulating pain perception, hedonic homeostasis, mood and wellbeing (1). Thus, they have long been the focus of physiological and [...]

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and µ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR (1). Although it shares high sequence similarity with classical opioid GPCR subtypes (~60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands (2,3). Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands., The pharmacological effects of NOP are complex and distinct from classical opioid receptors. N/OFQ shares sequence similarity with other opioid peptides, notably the κ-OR endogenous ligand dynorphin A, but does [...]

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR., The four opioid receptors, μ, δ, κ and the nociceptin/orphanin FQ peptide receptor, belong to the class A (rhodopsin-like) γ subfamily of G-protein-coupled receptors (GPCRs) (1) with a common seven-transmembrane [...]

Western blotting has been used to analyze lysates from cells expressing kappa-receptors tagged with a Flag to establish whether kappa-receptors exist as dimers. It was established that most kappa-receptors exist as dimers of relative molecular mass 130,000, irrespective of the presence or absence of a crosslinker. Research based on this finding provides biochemical and functional evidence for opioid-receptor heterodimerization. The heterodimers show greatly reduced affinities for their selective ligands.

The analgesic effect of opioids primarily activates the mu-opioid receptor but has a similar effect on the kappa-receptor, whose role is less clear. While kappa-receptors produce analgesia, they are also found to antagonize morphine analgesia. New research shows that the activation of the kappa-receptor specifically antagonizes analgesia induced by the mu-receptor. The finding suggest new approaches to the treatment of opioid addiction and pain control.

On a small table in his office at the Scripps Research Institute in La Jolla, California, Ray Stevens spreads out a sheet of paper covered with colourful branched lines, each [...]

Author Affiliations: 10.1016/j.cell.2009.04.019 Delta and mu opioid receptors regulate pain transmission in the nervous system. Morphine and some endogenous opioids act on mu receptors to relieve pain, for example. But [...]

Cell 137, 1148-1159 (2009) Delta and mu opioid receptors regulate pain transmission in the nervous system. Morphine and some endogenous opioids act on mu receptors to relieve pain, for example. [...]

Myrrh, a compound from shrubs of the genus Commiphora of the Burseraceae has two sesquiterpenes that produce analgesic effects. Naloxone inhibits the analgesic activity of myrrh, suggesting an interaction with brain opioid mechanisms. Furanoeudesma-1,3-diene, the major component of myrrh binds to opioid receptors in the membranes of the brain. The presence of other compounds in myrrh, whose effects have been unfavorable, probably caused the stoppage of the myrrh's use as a pain killer in favor of opioids.

A peptide which binds to the opioid receptor-like 1 (ORL1), extracted from rat's brain, increases the reactivity to pain. The sensitivity of the rat to pain decreases if the activity of ORL1 is suppressed. The peptide consists of 17 amino acids and posses a structure similar to dynorphin A. The precursor of the peptide is formed in the brain as a larger polyprotein molecule. This peptide has been named noniception and is the only peptide to bind to ORL1.