Opioid receptors: From binding sites to visible molecules in vivo

INSERM, U596, Illkirch F-67400, France
Neuropharmacology (Impact Factor: 5.11). 09/2008; 56 Suppl 1(Suppl. 1):205-12. DOI: 10.1016/j.neuropharm.2008.07.033
Source: PubMed


Opioid drugs such as heroin interact directly with opioid receptors whilst other addictive drugs, including marijuana, alcohol and nicotine indirectly activate endogenous opioid systems to contribute to their rewarding properties. The opioid system therefore plays a key role in addiction neurobiology and continues to be a primary focus for NIDA-supported research. Opioid receptors and their peptide ligands, the endorphins and enkephalins, form an extensive heterogeneous network throughout the central and peripheral nervous system. In addition to reward, opioid drugs regulate many functions such that opioid receptors are targets of choice in several physiological, neurological and psychiatric disorders. Because of the multiplicity and diversity of ligands and receptors, opioid receptors have served as an optimal model for G protein coupled receptor (GPCR) research. The isolation of opioid receptor genes opened the way to molecular manipulations of the receptors, both in artificial systems and in vivo, contributing to our current understanding of the diversity of opioid receptor biology at the behavioral, cellular and molecular levels. This review will briefly summarize some aspects of current knowledge that has accumulated since the very early characterization of opioid receptor genes. Importantly, we will identify a number of research directions that are likely to develop during the next decade.

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Available from: Chris Evans, Jun 14, 2014
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    • "Since the discovery of enkephalins in 1975 [12] thousands of opioid analogs have been synthesized to understand the relationship between their conformation and bioactivity, and to improve their pharmacological profile. Leu-enkephalin and Metenkephalin are involved in many physiological processes, their roles in behavior, neuroendocrinology and pain transmission being well documented [15] [32]. The use of enkephalins in pain treatment has been limited by the lack of metabolic stability and bioavailability [2]. "
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    ABSTRACT: Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for μ and δ-opioid receptors, and a significant to κ-receptor. The paper reports the synthesis of novel analogues of biphalin containing β(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker. The potency and selectivity of the peptides were evaluated by a competitive receptor-binding assay in rat brain homogenate using [(3)H]DAMGO (a μ ligand) and [(3)H]DELT (a δ ligand). Analogs with β(3)-h-p-NO2Phe in positions 4 and 4' are the most active compounds. Selectivity depends on the degree of freedom between the two pharmacophore moieties. Analogs with a hydrazine linker show noticeable binding selectivity to μ receptors (IC50(μ)=0.72nM; IC50(δ) =4.66nM), while the peptides with a 1,2-phenylenediamine linker show slight δ selectivity (IC50(μ)=10.97nM; IC50(δ) =1.99nM). Tyr-D-Ala-Gly-β(3)-h-p-NO2PheNHNH-β(3)-h-p-NO2Phe (1) and (Tyr-D-Ala-Gly-β(3)-h-p-NO2PheNH)2 (2) produced greater antinociceptive effect compared to morphine after i.t. administration. Copyright © 2015. Published by Elsevier Inc.
    Peptides 02/2015; 66. DOI:10.1016/j.peptides.2015.02.004 · 2.62 Impact Factor
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    • "MHb expresses remarkably high levels of mu opioid receptors (MORs). This G-protein-coupled receptor belongs to the opioid system, which plays a major role in pain control and autonomic functions, and modulates affective behavior and neuroendocrine physiology (Kieffer and Evans, 2009; Lutz and Kieffer, 2013). The MOR has unambiguously been established as the molecular target for opiate drugs, and mediates all the biological activities of morphine including both therapeutic and adverse effects (Matthes et al., 1996; Charbogne et al., 2014). "
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    ABSTRACT: The habenular complex, encompassing medial (MHb) and lateral (LHb) divisions, is a highly conserved epithalamic structure involved in the dorsal diencephalic conduction system (DDC). These brain nuclei regulate information flow between the limbic forebrain and the mid- and hindbrain, integrating cognitive with emotional and sensory processes. The MHb is also one of the strongest expression sites for mu opioid receptors (MORs), which mediate analgesic and rewarding properties of opiates. At present however, anatomical distribution and function of these receptors have been poorly studied in MHb pathways. Here we took advantage of a newly generated MOR-mcherry knock-in mouse line to characterize MOR expression sites in the DDC. MOR-mcherry fluorescent signal is weak in the lateral habenula, but strong expression is visible in the medial habenula, fasciculus retroflexus and interpeduncular nucleus (IPN), indicating that MOR is mainly present in the MHb-IPN pathway. MOR-mcherry cell bodies are detected both in basolateral and apical parts of MHb, where the receptor co-localizes with cholinergic and Substance P (SP) neurons, respectively, representing two main MHb neuronal populations. MOR-mcherry is expressed in most MHb-SP neurons, and is present in only a subpopulation of MHb-cholinergic neurons. Intense diffuse fluorescence detected in lateral and rostral parts of the IPN further suggests that MOR-mcherry is transported to terminals of these SP and cholinergic neurons. Finally, MOR-mcherry is present in septal regions projecting to the MHb, and in neurons of the central and intermediate IPN. Together, this study describes MOR expression in several compartments of the MHb-IPN circuitry. The remarkably high MOR density in the MHb-IPN pathway suggests that these receptors are in a unique position to mediate analgesic, autonomic and reward responses.
    Neuroscience 07/2014; 277. DOI:10.1016/j.neuroscience.2014.07.053 · 3.36 Impact Factor
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    • "Among the three opioid receptor types, μ (MOP), δ (DOP) and κ (KOP), the MOP receptor is the main type involved in modulation of pain perception, and it has the most clinical value in pharmacotherapy of pain with opioid analgesics [4]. Similar to the other two receptors, DOP and KOP, the MOP receptor displays the topology characteristics of the rhodopsin family of G protein-coupled receptors (GPCRs) with seven transmembrane loops [5], and is expressed at central and peripheral sites within the pain control circuits. An important milestone in the opioid field, represented by elucidation of the MOP receptor structure, was recently reached [6]. "
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    ABSTRACT: Background Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. Results This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. Conclusion Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.
    Molecular Pain 07/2014; 10(1):48. DOI:10.1186/1744-8069-10-48 · 3.65 Impact Factor
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