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Neuroscience Dec 2016In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their... (Review)
Review
In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.
Topics: Animals; Cell Line; Humans; Mice, Transgenic; Receptors, Opioid, delta; Research Design
PubMed: 27349452
DOI: 10.1016/j.neuroscience.2016.06.028 -
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 -
PloS One 2020Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved...
Kratom is a botanical substance that is marketed and promoted in the US for pharmaceutical opioid indications despite having no US Food and Drug Administration approved uses. Kratom contains over forty alkaloids including two partial agonists at the mu opioid receptor, mitragynine and 7-hydroxymitragynine, that have been subjected to the FDA's scientific and medical evaluation. However, pharmacological and toxicological data for the remaining alkaloids are limited. Therefore, we applied the Public Health Assessment via Structural Evaluation (PHASE) protocol to generate in silico binding profiles for 25 kratom alkaloids to facilitate the risk evaluation of kratom. PHASE demonstrates that kratom alkaloids share structural features with controlled opioids, indicates that several alkaloids bind to the opioid, adrenergic, and serotonin receptors, and suggests that mitragynine and 7-hydroxymitragynine are the strongest binders at the mu opioid receptor. Subsequently, the in silico binding profiles of a subset of the alkaloids were experimentally verified at the opioid, adrenergic, and serotonin receptors using radioligand binding assays. The verified binding profiles demonstrate the ability of PHASE to identify potential safety signals and provide a tool for prioritizing experimental evaluation of high-risk compounds.
Topics: Animals; Binding Sites; HEK293 Cells; Humans; In Vitro Techniques; Mitragyna; Molecular Docking Simulation; Plants, Medicinal; Radioligand Assay; Receptors, Adrenergic; Receptors, Opioid; Receptors, Opioid, mu; Receptors, Serotonin; Secologanin Tryptamine Alkaloids; Structure-Activity Relationship
PubMed: 32126112
DOI: 10.1371/journal.pone.0229646 -
Pharmacology & Therapeutics May 2022Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ... (Review)
Review
Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating four opioid receptors, namely μ (mu, MOP), δ (delta, DOP), κ (kappa, KOP) and the nociceptin/orphanin FQ receptor (NOP). Interestingly, several other receptors are also activated by endogenous opioid peptides and influence opioid-driven signaling and biology. However, they do not meet the criteria to be recognized as classical opioid receptors, as they are phylogenetically distant from them and are insensitive to classical non-selective opioid receptor antagonists (e.g. naloxone). Nevertheless, accumulating reports suggest that these receptors may be interesting alternative targets, especially for the development of safer analgesics. Five of these opioid peptide-binding receptors belong to the family of G protein-coupled receptors (GPCRs)-two are members of the Mas-related G protein-coupled receptor X family (MrgX1, MrgX2), two of the bradykinin receptor family (B B), and one is an atypical chemokine receptor (ACKR3). Additionally, the ion channel N-methyl-d-aspartate receptors (NMDARs) are also activated by opioid peptides. In this review, we recapitulate the implication of these alternative receptors in opioid-related disorders and discuss their unconventional biology, with members displaying signaling to scavenging properties. We provide an overview of their established and emerging roles and pharmacology in the context of pain management, as well as their clinical relevance as alternative targets to overcome the hurdles of chronic opioid use. Given the involvement of these receptors in a wide variety of functions, including inflammation, chemotaxis, anaphylaxis or synaptic transmission and plasticity, we also discuss the challenges associated with the modulation of both their canonical and opioid-driven signaling.
Topics: Analgesics, Opioid; Biology; Humans; Narcotic Antagonists; Opioid Peptides; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 34624426
DOI: 10.1016/j.pharmthera.2021.108014 -
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 -
The Journal of Neuroscience : the... Mar 2023The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors,...
Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Knock-in Rats.
The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between knock-in rats and wildtype littermates. HCR-FISH assay showed that is highly coexpressed with (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male rats and had a stronger inhibitory effect on the effort to self-administer heroin in female rats. The validation of an knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats. The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.
Topics: Rats; Male; Female; Animals; Heroin; Analgesics, Opioid; Nucleus Accumbens; Receptors, Opioid; Rats, Transgenic; Receptors, Opioid, mu; Pain; Heroin Dependence
PubMed: 36717230
DOI: 10.1523/JNEUROSCI.2049-22.2023 -
Journal of Medicinal Chemistry May 2021The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor...
The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt,Xaa]N/OFQ(1-13)-NH were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr and Thr at the N-terminal portion of N/OFQ(1-13)-NH with the noncanonical amino acid Dmt. [Dmt]N/OFQ(1-13)-NH has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an model of cough.
Topics: Animals; Binding Sites; Cough; Disease Models, Animal; Guinea Pigs; Humans; Hydrophobic and Hydrophilic Interactions; Male; Molecular Dynamics Simulation; Peptides; Receptors, Opioid; Receptors, Opioid, mu; Recombinant Proteins; Structure-Activity Relationship; Nociceptin Receptor
PubMed: 33998786
DOI: 10.1021/acs.jmedchem.0c02062 -
Journal of Oral Science 2017The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic... (Review)
Review
The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic activity in the nucleus accumbens by activating δ- and μ-opioid receptors in the ventral tegmental area. However, δ- and μ-opioid receptor agonists increase extracellular levels of accumbal dopamine when infused directly into the nucleus accumbens of rats. Therefore, the roles of δ- and μ-opioid receptors in regulation of accumbal dopaminergic neural activity have been analyzed by using δ- and μ-opioid receptor ligands. This review describes the mechanisms underlying the stimulatory effects on accumbal dopamine efflux, which are induced by local administration of δ- and μ-opioid receptor agonists into the nucleus accumbens of freely moving rats. The focus of this article is neurochemical studies that use in vivo microdialysis techniques. Taken together, the in vivo neurochemical evidence from these studies indicates that δ- and μ-opioid receptor agonists increase accumbal dopamine efflux by activating naloxone-sensitive opioid receptors, and by mechanisms independent of naloxone-sensitive opioid receptors, in the nucleus accumbens.
Topics: Animals; Dopamine; Extracellular Space; Nucleus Accumbens; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 28637978
DOI: 10.2334/josnusd.16-0874 -
Anesthesiology Sep 2021Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid...
BACKGROUND
Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates.
METHODS
The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses.
RESULTS
Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches).
CONCLUSIONS
In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Fentanyl; Indoles; Injections, Spinal; Macaca mulatta; Male; Opioid Peptides; Pain Measurement; Receptors, Opioid; Receptors, Opioid, mu; Spiro Compounds; Nociceptin Receptor; Nociceptin
PubMed: 34237134
DOI: 10.1097/ALN.0000000000003848 -
Trends in Pharmacological Sciences Nov 2017Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or... (Review)
Review
Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics.
Topics: Analgesics, Opioid; Animals; Drug Design; Humans; Receptors, Opioid, mu
PubMed: 28935293
DOI: 10.1016/j.tips.2017.08.004