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British Journal of Pharmacology Jan 2015The efficiency of μ-opioid receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation of intracellular serine and threonine... (Review)
Review
UNLABELLED
The efficiency of μ-opioid receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation of intracellular serine and threonine residues. Here, we review and discuss recent progress in the generation and application of phosphosite-specific μ-opioid receptor antibodies, which have proved to be excellent tools for monitoring the spatial and temporal dynamics of receptor phosphorylation and dephosphorylation. Agonist-induced phosphorylation of μ-opioid receptors occurs at a conserved 10 residue sequence (370) TREHPSTANT(379) in the receptor's carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at S375, present in the middle of this sequence, but only high-efficacy opioids have the ability to drive higher order phosphorylation on flanking residues (T370, T376 and T379). S375 is the initiating residue in a hierarchical phosphorylation cascade. In contrast, agonist-independent heterologous μ-opioid receptor phosphorylation occurs primarily at T370. The combination of phosphosite-specific antibodies and siRNA knockdown screening also facilitated the identification of relevant kinases and phosphatases. In fact, morphine induces a selective S375 phosphorylation that is predominantly catalysed by GPCR kinase 5 (GRK5), whereas multisite phosphorylation induced by high-efficacy opioids specifically requires GRK2/3. By contrast, T370 phosphorylation stimulated by phorbol esters or heterologous activation of Gq -coupled receptors is mediated by PKCα. Rapid μ-opioid receptor dephosphorylation occurs at or near the plasma membrane and is catalysed by protein phosphatase 1γ (PP1γ). These findings suggest that there are distinct phosphorylation motifs for homologous and heterologous regulation of μ-opioid receptor phosphorylation. However, it remains to be seen to what extent different μ-opioid receptor phosphorylation patterns contribute to the development of tolerance and dependence in vivo.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Topics: Animals; Humans; Phosphorylation; Receptors, Opioid, mu
PubMed: 24517854
DOI: 10.1111/bph.12627 -
Journal of Cellular Physiology May 2016Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the... (Review)
Review
Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology.
Topics: Analgesics, Opioid; HIV Infections; Humans; Protein Isoforms; RNA Splicing; Receptors, Opioid; Structure-Activity Relationship
PubMed: 26529364
DOI: 10.1002/jcp.25237 -
British Journal of Pharmacology Jul 2018The endogenous opioid system is well known to relieve pain and underpin the rewarding properties of most drugs of abuse. Among opioid receptors, the μ receptor mediates... (Review)
Review
The endogenous opioid system is well known to relieve pain and underpin the rewarding properties of most drugs of abuse. Among opioid receptors, the μ receptor mediates most of the analgesic and rewarding properties of opioids. Based on striking similarities between social distress, physical pain and opiate withdrawal, μ receptors have been proposed to play a critical role in modulating social behaviour in humans and animals. This review summarizes experimental data demonstrating such role and proposes a novel model, the μ opioid receptor balance model, to account for the contribution of μ receptors to the subtle regulation of social behaviour. Interestingly, μ receptor null mice show behavioural deficits similar to those observed in patients with autism spectrum disorder (ASD), including severe impairment in social interactions. Therefore, after a brief summary of recent evidence for blunted (social) reward processes in subjects with ASD, we review here arguments for altered μ receptor function in this pathology. This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.
Topics: Animals; Autism Spectrum Disorder; Humans; Receptors, Opioid, mu; Reward; Social Behavior
PubMed: 28369738
DOI: 10.1111/bph.13808 -
Molecular Pharmacology May 2019Opioids serve a vital role in the current analgesic array of treatment options. They are useful in acute instances involving severe pain associated with trauma, surgery,... (Review)
Review
Opioids serve a vital role in the current analgesic array of treatment options. They are useful in acute instances involving severe pain associated with trauma, surgery, and terminal diseases such as cancer. In the past three decades, multiple receptor isoforms and conformations have been reported throughout literature. Most of these studies conducted systemic analyses of opioid receptor function, often generalizing findings from receptor systems in central nervous tissue or exogenously expressing immortalized cell lines as common mechanisms throughout physiology. However, a culmination of innovative experimental data indicates that opioid receptor systems are differentially modulated depending on their anatomic expression profile. Importantly, opioid receptors expressed in the peripheral nervous system undergo regulation uncommon to similar receptors expressed in central nervous system tissues. This distinctive characteristic begs one to question whether peripheral opioid receptors maintain anatomically unique roles, and whether they may serve an analgesic advantage in providing pain relief without promoting addiction.
Topics: Analgesics, Opioid; Animals; Central Nervous System; Humans; Pain; Peripheral Nervous System; Receptors, Opioid
PubMed: 30723091
DOI: 10.1124/mol.118.114637 -
British Journal of Pharmacology Jan 2015Opioid receptors are highly homologous GPCRs that modulate brain function at all levels of neural integration, including autonomous, sensory, emotional and cognitive... (Review)
Review
UNLABELLED
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.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Topics: Analgesics, Opioid; Animals; Drug Discovery; Humans; Protein Multimerization; Receptors, Opioid
PubMed: 24666391
DOI: 10.1111/bph.12702 -
Molecules (Basel, Switzerland) Jan 2022In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing... (Review)
Review
In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing their adverse effects. Throughout the extent of development for new pain therapies, the nociceptin/orphanin FQ receptor (NOP receptor) has appeared to be an encouraging focal point. Concentrating on NOP receptor to treat chronic pain with limited range of unwanted effects serves as a suitable alternative to prototypical opioid morphine that could potentially lead to life-threatening effects caused by respiratory depression in overdose, as well as generate abuse and addiction. In addition to these harmful effects, the uprising opioid epidemic is responsible for becoming one of the most disastrous public health issues in the US. In this article, the contributing molecular and cellular structure in controlling the cellular trafficking of NOP receptor and studies that support the role of NOP receptor and its ligands in pain management are reviewed.
Topics: Animals; Humans; Ligands; Narcotic Antagonists; Pain; Receptors, Opioid; Nociceptin Receptor
PubMed: 35163856
DOI: 10.3390/molecules27030595 -
Trends in Pharmacological Sciences Apr 2016Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an... (Review)
Review
Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled palette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemogenetic and optogenetic tools, and new mouse lines, are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics.
Topics: Animals; Humans; Molecular Docking Simulation; Nerve Net; Receptors, Opioid
PubMed: 26833118
DOI: 10.1016/j.tips.2016.01.001 -
Neuropharmacology Jan 2014Opioids have an important place in pharmacology. While their clinical use as analgesics is fundamental in medicine, their use is constrained by their side-effects and... (Review)
Review
Opioids have an important place in pharmacology. While their clinical use as analgesics is fundamental in medicine, their use is constrained by their side-effects and abuse potential. Pharmacologists have sought analgesics lacking side-effects and the abuse liability of the current agents. The identification of the opioid receptors in 1973 marked the beginning of our understanding of the molecular mechanisms of these agents. The isolation of the opioid peptides quickly followed, along with the classification of three families of opioid receptors. Clinicians have long been aware of subtle differences among the mu opioids that were not easily reconciled with a single receptor and selective antagonists implied two subdivisions of mu receptors. However, the cloning of the mu opioid receptor MOR-1 has led to the realization of the extensive complexity of the mu opioid receptor gene and its vast array of splice variants. Many of these splice variants are truncated and do not conform to the structure of traditional G-protein coupled receptors. Yet, evidence now shows that they are quite important and may prove valuable targets in the development of potent analgesics lacking the undesirable properties of current opioids. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Topics: Analgesics, Opioid; Animals; Humans; Receptors, Opioid
PubMed: 23624289
DOI: 10.1016/j.neuropharm.2013.03.039 -
Pharmacological Research Nov 2023Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs,... (Review)
Review
Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI's. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest.
Topics: Humans; Analgesics, Opioid; Receptors, Opioid, mu; Receptors, Opioid, kappa; Receptors, Opioid; Acute Pain
PubMed: 37844653
DOI: 10.1016/j.phrs.2023.106961 -
Cellular Immunology 2008Opioids were originally discovered because of their ability to induce analgesia, but further investigation has shown that the opioids regulate the function of cells... (Review)
Review
Opioids were originally discovered because of their ability to induce analgesia, but further investigation has shown that the opioids regulate the function of cells involved in the immune response. We suggest that the regulation of cytokine, chemokine, and cytokine receptor expression is a critical component of the immunomodulatory activity of the opioids. In this paper we review the literature dealing with the regulation of cytokine and cytokine receptor expression by agonists for the three major opioid receptor types (mu, kappa, and delta), and nociceptin, the natural agonist for the orphanin FQ/nociceptin receptor. Although the opioid receptors share a high degree of sequence homology, opposing roles between the kappa opioid receptor (KOR) and the mu opioid receptor (MOR) have become apparent. We suggest that activation of the KOR induces an anti-inflammatory response through the down-regulation of cytokine, chemokine and chemokine receptor expression, while activation of the MOR favors a pro-inflammatory response. Investigation into the opioid receptor-like (ORL1)/nociceptin system also suggests a role for this receptor as a down-regulator of immune function. These effects suggest a broad role for opioids in the modulation of the function of the immune system, and suggest possible targets for the development of new therapeutics for inflammatory and infectious diseases.
Topics: Animals; Humans; Opioid Peptides; Receptors, Cytokine; Receptors, Opioid; Nociceptin Receptor; Nociceptin
PubMed: 18279847
DOI: 10.1016/j.cellimm.2007.09.008