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Drug Design, Development and Therapy 2023Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to... (Review)
Review
Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to chronic pain. Opioids have traditionally been the mainstay for treatment of moderate to severe acute pain. However, their use has been associated with opioid-related adverse events (ORAEs), such as respiratory depression, sedation, nausea, vomiting, pruritus, and decreased bowel motility. In addition, their liberal use has been implicated in the current opioid epidemic. As a result, there has been renewed interest in multimodal analgesia to target different mechanisms of action in order to achieve a synergistic effect and minimize opioid usage. Oliceridine is a novel mu-opioid receptor agonist that is part of a new class of biased ligands that selectively activate G-protein signaling and downregulate β-arrestin recruitment. Since G-protein signaling has been associated with analgesia while β-arrestin recruitment has been associated with ORAEs, there is potential for a wider therapeutic window. In this review, we will discuss the clinical evidence behind oliceridine and its potential role in acute postoperative pain management. We have systematically searched the PubMed database using the keywords , and . All articles identified were reviewed and evaluated, and all clinical trials were included.
Topics: Humans; Analgesics, Opioid; Morphine; Pain, Postoperative; GTP-Binding Proteins
PubMed: 36987403
DOI: 10.2147/DDDT.S372612 -
European Journal of Medicinal Chemistry Dec 2022Kappa opioid receptor (KOR) is a member of the opioid receptor system, the G protein-coupled receptors that are expressed throughout the peripheral and central nervous... (Review)
Review
Kappa opioid receptor (KOR) is a member of the opioid receptor system, the G protein-coupled receptors that are expressed throughout the peripheral and central nervous systems and play crucial roles in the modulation of antinociception and a variety of behavioral states like anxiety, depression, and drug abuse. KOR agonists are known to produce potent analgesic effects and have been used clinically for the treatment of pain, while KOR antagonists have shown efficacy in the treatment of anxiety and depression. This review summarizes the history, design strategy, discovery, and development of KOR ligands. KOR agonists are classified as non-biased, G protein-biased, and β-arrestin recruitment-biased, according to their degrees of bias. The mechanisms and associated effects of the G protein signaling pathway and β-arrestin recruitment signaling pathway are also discussed. Meanwhile, KOR antagonists are classified as long-acting and short-acting, based on their half-lives. In addition, we have special sections for mixed KOR agonists and selective peripheral KOR agonists. The mechanisms of action and pharmacokinetic, pharmacodynamic, and behavioral studies for each of these categories are also discussed in this review.
Topics: Humans; Receptors, Opioid, kappa; Depression; Ligands; beta-Arrestins; GTP-Binding Proteins; Narcotic Antagonists; Pain; Anxiety; Substance-Related Disorders; Analgesics, Opioid
PubMed: 36179400
DOI: 10.1016/j.ejmech.2022.114785 -
International Journal of Molecular... Mar 2023Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain... (Review)
Review
Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.
Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics' receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.
Topics: Humans; Antipsychotic Agents; Dopamine; Schizophrenia; Schizophrenia, Treatment-Resistant; beta-Arrestins
PubMed: 36983018
DOI: 10.3390/ijms24065945