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Pharmacological Reviews Nov 2023Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used... (Review)
Review
Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the -opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a -opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.
Topics: Animals; Humans; Oxycodone; Thebaine; Analgesics, Opioid; Opioid-Related Disorders; Morphine; Receptors, Opioid
PubMed: 37321860
DOI: 10.1124/pharmrev.121.000506 -
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 -
Revue Medicale Suisse Aug 2023
Topics: Humans; Opiate Alkaloids; Low Back Pain; Neck Pain; Acute Pain
PubMed: 37610198
DOI: 10.53738/REVMED.2023.19.838.1530 -
Revue Medicale Suisse Oct 2023
Topics: Humans; Opiate Alkaloids; Neck Pain
PubMed: 37850812
DOI: 10.53738/REVMED.2023.19.846.1959 -
Revue Medicale Suisse Jan 2024
Topics: Humans; Opiate Alkaloids; Pain Management
PubMed: 38268354
DOI: 10.53738/REVMED.2024.20.858.130 -
CJEM Oct 2023
Topics: Humans; Buprenorphine, Naloxone Drug Combination; Buprenorphine; Emergency Service, Hospital; Analgesics, Opioid
PubMed: 37805957
DOI: 10.1007/s43678-023-00594-z -
Brain, Behavior, and Immunity Oct 2023Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous...
Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous researches have shown that astrocytes contribute to brain diseases, the role of astrocyte in morphine addiction through induced neuroinflammation remain unexplored. Here we show that morphine-induced inflammation requires the crosstalk among neuron, astrocyte, and microglia. Specifically, astrocytes respond to morphine-induced neuronal activation by increasing glycolytic metabolism. The dysregulation of glycolysis leads to an increased in the generation of mitochondrial reactive oxygen species and causes excessive mitochondrial fragmentation in astrocytes. These fragmented, dysfunctional mitochondria are consequently released into extracellular environment, leading to activation of microglia and release of inflammatory cytokines. We also found that blocking the nicotinamide adenine dinucleotide salvage pathway with FK866 could inhibit astrocytic glycolysis and restore the mitochondrial homeostasis and effectively attenuate neuroinflammatory responses. Importantly, FK866 reversed morphine-induced addictive behaviors in mice. In summary, our findings illustrate an essential role of astrocytic immunometabolism in morphine induced neural and behavioral plasticity, providing a novel insight into the interactions between neurons, astrocytes, and microglia in the brain affected by chronic morphine exposure.
Topics: Mice; Animals; Morphine Dependence; Astrocytes; Neuroinflammatory Diseases; Morphine; Microglia; Mitochondria
PubMed: 37543246
DOI: 10.1016/j.bbi.2023.07.030 -
Neuron Dec 2023Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate...
Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
Topics: Analgesics, Opioid; Oxymorphone; Pharmaceutical Preparations; Dopamine; Naloxone; Receptors, Opioid, mu
PubMed: 37848025
DOI: 10.1016/j.neuron.2023.09.017 -
American Journal of Surgery Oct 2023
Topics: Humans; Opium; Opiate Alkaloids; Opioid-Related Disorders
PubMed: 37336710
DOI: 10.1016/j.amjsurg.2023.06.007 -
Frontiers in Public Health 2023Opioid use disorder (OUD) is a major public health threat, contributing to morbidity and mortality from addiction, overdose, and related medical conditions. Despite our... (Review)
Review
Opioid use disorder (OUD) is a major public health threat, contributing to morbidity and mortality from addiction, overdose, and related medical conditions. Despite our increasing knowledge about the pathophysiology and existing medical treatments of OUD, it has remained a relapsing and remitting disorder for decades, with rising deaths from overdoses, rather than declining. The COVID-19 pandemic has accelerated the increase in overall substance use and interrupted access to treatment. If increased naloxone access, more buprenorphine prescribers, greater access to treatment, enhanced reimbursement, less stigma and various harm reduction strategies were effective for OUD, overdose deaths would not be at an all-time high. Different prevention and treatment approaches are needed to reverse the concerning trend in OUD. This article will review the recent trends and limitations on existing medications for OUD and briefly review novel approaches to treatment that have the potential to be more durable and effective than existing medications. The focus will be on promising interventional treatments, psychedelics, neuroimmune, neutraceutical, and electromagnetic therapies. At different phases of investigation and FDA approval, these novel approaches have the potential to not just reduce overdoses and deaths, but attenuate OUD, as well as address existing comorbid disorders.
Topics: Humans; Pandemics; Opiate Substitution Treatment; Opioid-Related Disorders; Buprenorphine; Naloxone; Drug Overdose
PubMed: 38332941
DOI: 10.3389/fpubh.2023.1274719