oxycodone IR (PFR06158) / Ensysce Biosciences - LARVOL DELTA

Spontaneous oxycodone withdrawal disrupts sleep, diurnal, and electrophysiological dynamics in rats. (PubMed, PLoS One) - "These findings suggest temporally dependent withdrawal effects on sleep, reflecting the complex way in which the allostatic forces of opioid withdrawal impinge upon sleep and diurnal processes. These foundational data based on continuous tracking of vigilance state, sleep stage composition, and spectral EEG properties provide a detailed construct with which to form and test hypotheses on the mechanisms of opioid-sleep interactions."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Insomnia • Sleep Disorder • Substance Abuse

Identification of unique microbiome and metabolome profiles associated with vulnerability to substance use disorder risk in a population of heterogenous outbred stock of rats using machine learning. (Neuroscience 2022) - "Upon supplementation of microbial metabolites in the oxycodone group, the vulnerable animals decreased their drug intake. These data demonstrate that microbial metabolic activity and functional read-outs such as metabolomics are key in developing novel diagnostics and therapeutics for substance use disorders."

Preclinical • CNS Disorders • Psychiatry • Substance Abuse

EGR3 regulates opioid-related nociception and motivation in male rats. (PubMed, Psychopharmacology (Berl)) - "Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Immunology • Inflammation • Pain • Psychiatry

Distinct Synaptic Vesicle Proteomic Signatures Associated with Pre- and Post-Natal Oxycodone-Exposure. (PubMed, Cells) - "Their respective differential expression was further validated by Western blot. In summary, our current study shows exposure to oxy in utero and postnatally can impact the SV proteome in the exposed offspring and the identification of these distinct SV signatures could further pave the way to further elucidate their downstream mechanisms including developing them as potential therapeutic targets."

Journal • Addiction (Opioid and Alcohol) • MEGF8

Transcriptomic Profiling Reveals Mesolimbic Gene Targets Associated with Oxycodone-Seeking During Abstinence. (PubMed, FASEB J) - "The results of the present study identified unique differences in the transcriptomic landscape of key nodes in the mesolimbic circuitry following abstinence from saline or oxycodone self-administration. In addition, the shared differentially expressed genes within the opioid signaling pathway (i.e., GNAS) provide prioritized candidates for future pharmacotherapeutics aimed to help maintain abstinence from oxycodone and prevent relapse in OUD."

Journal • Substance Abuse • GNAS

Mimicking Oxycodone Use Disorder in rodents: Transcriptional and Biochemical Consequences in the Rat Brain (SOBP 2022) - "These findings also suggest that escalated oxycodone-induced MSK1/2-dependent histone phosphorylation might serve to regulate striatal AMPA gene expression. These observations offer potential avenues for interventions against oxycodone addiction."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

The Selective M1 Muscarinic Acetylcholine Receptor Antagonist VU0255035 Attenuates Opioid Drug Seeking Behaviors in Rat (SOBP 2022) - "The present data suggest a complex role for M1 mAChRs in modulating the mesocorticolimbic reward circuitry and the potential for development of M1 antagonists for the treatment of opioid use disorder. DISCLOSURE Click here to read the SOBP Conflict of Interest Disclosure Policy. Financial Relationships Disclosure No, I have nothing to disclose."

Late-breaking abstract • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Substance Abuse

Oxycodone Physical Dependence Promotes Gene Adaptations in the Brain Reward Pathway Under Neuropathic and Pain-Free States (ACNP 2021) - "Using a novel inhibitor for HDAC1/2, RCY1305, we treated mice with RCY1305 (3mg/kg i.p daily) during oxycodone administration and drug withdrawal for 5- weeks. Our findings suggest that chronic pain states exacerbate the behavioral and transcriptomic signatures of oxycodone withdrawal. Overall, our studies highlight intracellular pathways, thereby providing novel possibilities for treating oxycodone dependence under neuropathic and pain-free states."

Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Depression • Neuralgia • Pain • Psychiatry • Sleep Disorder • Substance Abuse

Egr3 is Essential for Opioid-Induced Regulation of Nociception and Maladaptive Motivation (ACNP 2021) - "Taken together, this demonstrates the role of Egr3 as a mediator of neuroadaptations that lie at the intersection of recreational versus prescription opioid use influencing nociception and escalated motivation."

Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Pain • Psychiatry • PCR

Oxycodone Physical Dependence Promotes Gene Adaptations in the Brain Reward Pathway Under Neuropathic and Pain-Free States (ACNP 2021) - "Using a novel inhibitor for HDAC1/2, RCY1305, we treated mice with RCY1305 (3mg/kg i.p daily) during oxycodone administration and drug withdrawal for 5- weeks. Our findings suggest that chronic pain states exacerbate the behavioral and transcriptomic signatures of oxycodone withdrawal. Overall, our studies highlight intracellular pathways, thereby providing novel possibilities for treating oxycodone dependence under neuropathic and pain-free states."

Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Depression • Neuralgia • Pain • Psychiatry • Sleep Disorder • Substance Abuse

Egr3 is Essential for Opioid-Induced Regulation of Nociception and Maladaptive Motivation (ACNP 2021) - "Taken together, this demonstrates the role of Egr3 as a mediator of neuroadaptations that lie at the intersection of recreational versus prescription opioid use influencing nociception and escalated motivation."

Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Pain • Psychiatry • PCR

Integrated Systems Analysis of Mixed Neuroglial Cultures Proteome Post Oxycodone Exposure. (PubMed, Int J Mol Sci) - "Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function."

Journal • CNS Disorders • Depression • Psychiatry

[VIRTUAL] Effect of Naloxegol on Opioid-Induced Esophageal Motility Disorder (ACG 2020) - " Naloxegol could successfully decrease DCI in our 2 patient with opioid induced esophageal disorders and change esophageal manometric signatures favorably with improvement in clinical symptoms. Larger studies are needed with different opioids to study and confirm dose- effect relationships."

Addiction (Opioid and Alcohol) • Constipation • Gastroenterology • Gastrointestinal Disorder • Rare Diseases

Mechanisms of interleukin 4 mediated increase in efficacy of vaccines against opioid use disorders. (PubMed, NPJ Vaccines) - "Using immunomodulation of cytokine signaling to increase vaccine efficacy, this study found that blocking IL-4 improved the efficacy of vaccines targeting oxycodone and fentanyl in male and female mice. Enhancement of vaccine efficacy with blockade of IL-4 was associated with improved germinal center formation in secondary lymphoid organs and selective transcriptome signatures in the activated CD4 T cell population subset. These data suggest that IL-4 is both a pharmacological target and a potential biomarker of vaccine efficacy against OUD."

Clinical • Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Immune Modulation • Immunology • Inflammation • Psychiatry • IL13 • IL4 • STAT6

[VIRTUAL] Oxycodone-Induced Gene Adaptations in the Brain Reward Center in a Murine Model of Neuropathic Pain (ACNP 2020) - "Our findings suggest that chronic pain states exacerbate the behavioral and transcriptomic signatures of oxycodone withdrawal. Overall this work will provide new insights on the influence of long term pain in oxycodone-induced plasticity in the brain reward center. We are also evaluating if interventions in several genes or intracellular pathways may effectively alleviate oxycodone physical dependence in pain free or in chronic pain states."

Preclinical • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Depression • Mood Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • Psychiatry • Sleep Disorder

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure. (PubMed, Cells) - "Further treatment of primary 14-day in vitro (DIV) neurons with IUO BDEs caused a significant reduction in spine density compared to treatment with BDEs from PNO and saline groups. In summary, our studies identified for the first time, key BDE miRNA signatures in IUO- and PNO-exposed offspring, which could impact their brain development as well as synaptic function."

Journal • Pain

Sex Differences in Opioid Addiction Sensitivity (ACNP 2018) - "We find a number of sex-dependent molecular responses to oxycodone self-administration and withdrawal, including altered microRNA expression in the bed nucleus of the stria terminalis and altered c-Fos induction in the nucleus accumbens and paraventricular nucleus of the thalamus. Although much work needs to be done to causally link these molecular signatures with addictive-like behavior, we will present the data at hand and how we and the field can use it to advance our understanding of the biological basis of sex differences in OUD"

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Pain

Oxycodone-Mediated Activation of the Mu Opioid Receptor Reduces Whole Brain Functional Connectivity in Mice. (PubMed, ACS Pharmacol Transl Sci) - "In conclusion, we demonstrate that oxycodone reduces brain communication in a MOR-dependent manner, and establish a preliminary whole-brain FC signature of oxycodone. This proof-of-principle study provides a unique platform and reference data set to test other MOR opioid agonists and perhaps discover new mechanisms and FC biomarkers predicting safer analgesics."

Journal • Preclinical • MRI

Circulating miRNA Signature as a Potential Biomarker for the Prediction of Analgesic Efficacy of Hydromorphone. (PubMed, Int J Mol Sci) - "A significant correlation was observed between the analgesic efficacy and the putative MOR signal level, and patients with low MOR signal achieved better pain control (i.e., ΔVAS < 0) through hydromorphone. These results suggested that plasma miRNA signatures could serve as clinical biomarkers for the prediction of the analgesic efficacy of hydromorphone."

Biomarker • Clinical • Journal