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Neuropharmacology Jun 2023Neuroplasticity in cortico-limbic circuits has been implicated in pain persistence and pain modulation in clinical and preclinical studies. The amygdala has emerged as a... (Review)
Review
Neuroplasticity in cortico-limbic circuits has been implicated in pain persistence and pain modulation in clinical and preclinical studies. The amygdala has emerged as a key player in the emotional-affective dimension of pain and pain modulation. Reciprocal interactions with medial prefrontal cortical regions undergo changes in pain conditions. Other limbic and paralimbic regions have been implicated in pain modulation as well. The cortico-limbic system is rich in opioids and opioid receptors. Preclinical evidence for their pain modulatory effects in different regions of this highly interactive system, potentially opposing functions of different opioid receptors, and knowledge gaps will be described here. There is little information about cell type- and circuit-specific functions of opioid receptor subtypes related to pain processing and pain-related plasticity in the cortico-limbic system. The important role of anterior cingulate cortex (ACC) and amygdala in MOR-dependent analgesia is most well-established, and MOR actions in the mesolimbic system appear to be similar but remain to be determined in mPFC regions other than ACC. Evidence also suggests that KOR signaling generally serves opposing functions whereas DOR signaling in the ACC has similar, if not synergistic effects, to MOR. A unifying picture of pain-related neuronal mechanisms of opioid signaling in different elements of the cortico-limbic circuitry has yet to emerge. This article is part of the Special Issue on "Opioid-induced changes in addiction and pain circuits".
Topics: Humans; Analgesics, Opioid; Receptors, Opioid, mu; Pain; Receptors, Opioid; Limbic System
PubMed: 36944393
DOI: 10.1016/j.neuropharm.2023.109510 -
Peptides Jul 2021This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles... (Review)
Review
This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2019 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Topics: Analgesics, Opioid; Animals; Cancer Pain; Chronic Pain; Ethanol; Female; Humans; Memory; Opioid Peptides; Pain, Postoperative; Pregnancy; Receptors, Opioid; Sexual Behavior; Social Status; Stress, Psychological; Substance-Related Disorders
PubMed: 33831447
DOI: 10.1016/j.peptides.2021.170547 -
Peptides Jun 2023This paper is the forty-fourth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles... (Review)
Review
This paper is the forty-fourth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2021 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonizts and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Topics: Animals; Humans; Opioid Peptides; Receptors, Opioid; Analgesics, Opioid; Learning; Pain
PubMed: 36990387
DOI: 10.1016/j.peptides.2023.171004 -
Trends in Neurosciences Jun 2020Post-translational modifications (PTMs) are key events in signal transduction since they affect protein function by regulating their abundance and/or activity. PTMs... (Review)
Review
Post-translational modifications (PTMs) are key events in signal transduction since they affect protein function by regulating their abundance and/or activity. PTMs involve the covalent attachment of functional groups to specific amino acids. Since they tend to be generally reversible, PTMs serve as regulators of signal transduction pathways. G-protein-coupled receptors (GPCRs) are major signaling proteins that undergo multiple types of PTMs. In this Review, we focus on the opioid receptors, members of GPCR family A, and highlight recent advances in the field that have underscored the importance of PTMs in the functional regulation of these receptors. Since opioid receptor activity plays a central role in the development of tolerance and addiction to morphine and other drugs of abuse, understanding the molecular mechanisms regulating receptor activity is of fundamental importance.
Topics: Humans; Phosphorylation; Protein Processing, Post-Translational; Receptors, Opioid; Signal Transduction; Ubiquitination
PubMed: 32459993
DOI: 10.1016/j.tins.2020.03.011 -
Journal of Neuroscience Research Jan 2022Over the past several years, studies have highlighted the δ-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management. While exhibiting... (Review)
Review
Over the past several years, studies have highlighted the δ-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management. While exhibiting milder undesired effects than most currently prescribed opioids, its specific agonists elicit effective analgesic responses in numerous animal models of chronic pain, including inflammatory, neuropathic, diabetic, and cancer-related pain. However, as compared with the extensively studied μ-opioid receptor, the molecular mechanisms governing its trafficking remain elusive. Recent advances have denoted several significant particularities in the regulation of DOPr intracellular routing, setting it apart from the other members of the opioid receptor family. Although they share high homology, each opioid receptor subtype displays specific amino acid patterns potentially involved in the regulation of its trafficking. These precise motifs or "barcodes" are selectively recognized by regulatory proteins and therefore dictate several aspects of the itinerary of a receptor, including its anterograde transport, internalization, recycling, and degradation. With a specific focus on the regulation of DOPr trafficking, this review will discuss previously reported, as well as potential novel trafficking barcodes within the opioid and nociceptin/orphanin FQ opioid peptide receptors, and their impact in determining distinct interactomes and physiological responses.
Topics: Analgesics; Analgesics, Opioid; Animals; Chronic Pain; Opioid Peptides; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 34559903
DOI: 10.1002/jnr.24949 -
Peptides Feb 2020This paper is the fortieth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published... (Review)
Review
This paper is the fortieth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2017 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Topics: Analgesics, Opioid; Animals; Cancer Pain; Chronic Pain; Eating; Emotions; Female; Humans; Learning; Male; Memory; Opioid Peptides; Opioid-Related Disorders; Pregnancy; Receptors, Opioid; Stress, Physiological; Substance-Related Disorders; Nociceptin Receptor
PubMed: 31805297
DOI: 10.1016/j.peptides.2019.170223 -
Frontiers in Immunology 2021
Topics: Animals; Disease Susceptibility; Gene Expression Regulation; Humans; Immune System; Neuroimmunomodulation; Receptors, Opioid; Signal Transduction
PubMed: 35082800
DOI: 10.3389/fimmu.2021.832292 -
Cell Reports Feb 2023Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the...
Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain μ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity. Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.
Topics: Analgesics, Opioid; Corpus Striatum; Fentanyl; Receptors, Opioid; Affect; Receptors, Opioid, mu
PubMed: 36796365
DOI: 10.1016/j.celrep.2023.112089 -
Nature Communications Dec 2023Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of...
Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
Topics: Male; Mice; Animals; Receptors, Opioid, kappa; Ligands; Analgesics, Opioid; Receptors, Opioid, mu; Peptides, Cyclic
PubMed: 38052802
DOI: 10.1038/s41467-023-43718-w -
Advanced Biology Jul 2023Opioids are one of the most potent drugs for treating moderate to severe pain. Despite irrefutable clinical application in chronic pain management, the long-term use of... (Review)
Review
Opioids are one of the most potent drugs for treating moderate to severe pain. Despite irrefutable clinical application in chronic pain management, the long-term use of opioids has been increasingly questioned due to undesired side effects that demand attention. Opioids such as morphine mediate clinically relevant effects primarily through the µ-opioid receptor that go beyond their classical role as analgesics, causing potentially fatal side effects such as tolerance, dependence, and addiction. Furthermore, there is growing evidence that opioids affect immune system function, cancer progression, metastasis, and recurrence. Though a biological plausibility, the clinical evidence for the action of opioids on cancer is mixed, revealing a more complex picture as researchers struggle to establish a vital link between opioid receptor agonists, cancer progression, and suppression, or both. Thus, in light of the uncertainty of opioid effects on cancer, in this review, a focused overview of the role of opioid receptors in modulating cancer progression, their underlying signaling mechanisms, and the biological activity of opioid receptor agonists and antagonists is provided.
Topics: Humans; Analgesics, Opioid; Receptors, Opioid; Pain; Analgesics; Neoplasms; Drug-Related Side Effects and Adverse Reactions
PubMed: 37132160
DOI: 10.1002/adbi.202300102