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Peptides Nov 2023This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles... (Review)
Review
This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 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: Animals; Humans; Female; Pregnancy; Opioid Peptides; Analgesics, Opioid; Analgesia; Analgesics, Non-Narcotic; Drug Tolerance
PubMed: 37704079
DOI: 10.1016/j.peptides.2023.171095 -
The Journal of Clinical Investigation Sep 2023The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder...
The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal-evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type-specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.
Topics: Mice; Animals; Analgesics, Opioid; Nucleus Accumbens; Receptors, Dopamine D2; Morphine; Naloxone; Substance Withdrawal Syndrome; Receptors, Dopamine D1; Mice, Inbred C57BL
PubMed: 37561576
DOI: 10.1172/JCI163266 -
Kidney360 Dec 2023Opioids are a class of medications used in pain management. Unfortunately, long-term use, overprescription, and illicit opioid use have led to one of the greatest... (Review)
Review
Opioids are a class of medications used in pain management. Unfortunately, long-term use, overprescription, and illicit opioid use have led to one of the greatest threats to mankind: the opioid crisis. Accompanying the classical analgesic properties of opioids, opioids produce a myriad of effects including euphoria, immunosuppression, respiratory depression, and organ damage. It is essential to ascertain the physiological role of the opioid/opioid receptor axis to gain an in-depth understanding of the effects of opioid use. This knowledge will aid in the development of novel therapeutic interventions to combat the increasing mortality rate because of opioid misuse. This review describes the current knowledge of opioids, including the opioid epidemic and opioid/opioid receptor physiology. Furthermore, this review intricately relates opioid use to kidney damage, navigates kidney structure and physiology, and proposes potential ways to prevent opioid-induced kidney damage.
Topics: Humans; Analgesics, Opioid; Opioid-Related Disorders; Opioid Epidemic; Receptors, Opioid; Kidney
PubMed: 37927032
DOI: 10.34067/KID.0000000000000291 -
Frontiers in Pharmacology 2023Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with... (Review)
Review
Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors () localized to the central nervous system (). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin () is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT receptor ( ) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HTR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HTR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HTR agonists and/or 5-HTR positive allosteric modulators may provide a new pathway for 5-HTR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HTR agonists as therapeutics for OUD.
PubMed: 37886127
DOI: 10.3389/fphar.2023.1239159 -
Drugs Jun 2024Tegileridine () is a small molecule μ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain.... (Review)
Review
Tegileridine () is a small molecule μ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the β-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery.
Topics: Humans; Drug Approval; Pain, Postoperative; Receptors, Opioid, mu; Analgesics, Opioid; China; Thiophenes; Spiro Compounds
PubMed: 38771484
DOI: 10.1007/s40265-024-02033-4 -
Journal of Clinical Medicine Sep 2023Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced... (Review)
Review
Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. Management of opioid-induced constipation should begin with ensuring adequate hydration and electrolyte balance and encouraging patient mobilization. Other treatments may include laxatives, enemas, intestinal secretagogues, peripherally acting µ-opioid receptor antagonists, and manual disimpaction. Surgical intervention may be required for some patients as a salvage therapy in severe, refractory cases.
PubMed: 37834791
DOI: 10.3390/jcm12196148 -
Nature Communications Nov 2023Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat...
Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.
Topics: Male; Mice; Animals; Receptors, Opioid, kappa; Dynorphins; Depression; Claustrum; Signal Transduction; Mice, Inbred C57BL
PubMed: 38036497
DOI: 10.1038/s41467-023-43636-x -
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 -
Cureus Sep 2023Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently... (Review)
Review
Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient's age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision.
PubMed: 37790027
DOI: 10.7759/cureus.44583