Lucia Barrenechea
Research Mentor: Jessica Anand
Mentor Department: Pharmacology, Medicine
Author(s): Not Available
Session: Session 4 (1:00 PM – 1:50 PM)
Presentation Type: Oral Presentation
Abstract
Opioid Use Disorder (OUD) is a treatable chronic disease characterized by the inability to refrain from repetitive opioid use, affecting approximately 6.1 million individuals. (Center for Drug Evaluation and Research, 2024). A significant clinical barrier to the treatment of OUD is opioid withdrawal, which is characterized by substantial physical symptoms such as tachycardia, agitation, and anxiety, as well as nausea and vomiting (Bluthenthal et al., 2020). Patients are often unwilling to engage in treatment or harm-reduction strategies due to these aversive symptoms, which result in significantly increased chances of relapse. Two important opioid receptors are the mu-opioid receptor (MOR), which mediates analgesia, and the kappa-opioid receptor (KOR), which promotes withdrawal effects. We hypothesize that the use of the mu-opioid receptor positive allosteric modulator BMS122 may prove beneficial in mitigating opioid withdrawal while preserving analgesic effects. For the in vitro assay, membrane fractions prepared from ??brain homogenate samples or Chinese hamster ovary cells (CHO-hKOR) were stimulated with DAMGO or Dynorphine in a radioligand binding assay utilizing GTPy35S, which enables precise measurement of receptor-ligand interactions and receptor activation. Brain homogenates were prepared from C57 mice that underwent a tolerance paradigm. Male and Female mice (C57-BL/6J), aged 8-14 weeks, were given twice-daily ramped morphine injections i.p. (Intraperitoneally) for 5 days, with doses ranging from 20-80 mg/kg, respectively. The effective concentration at 50% of the maximum efficacy (EC50) for differences in potency was compared with the standard DAMGO or Dynorphine response curves and across the treated mouse groups. All runs were completed three times in duplicate runs (n=6), and EC50s were then averaged together. These data, taken together, suggest that BMS122 is a positive allosteric modulator at MOR and has no effect at KOR when stimulated by Dynorphin, potentially increasing analgesic effect without worsening withdrawal effects. With this in mind, our team has been pursuing further investigations with BMS122 to better understand the allosteric modulators’ relationship with opioid tolerance. These experiments, along with their parallel brain homogenate in vitro assay, are ongoing. Once the tolerance and brain homogenate assays are completed, our future directions will include assessing downstream signaling pathways in in vitro models of opioid dependence and withdrawal to evaluate the role of secondary signaling (e.g., cAMP accumulation, arrest signaling, etc.) modulated by BMS122 upon receptor stimulation. Both of which will further our studies’ principal aim of exploring BMS122’s potential therapeutic effects for individuals suffering from Opioid Use Disorder. References: Bluthenthal, R. N., Simpson, K., Ceasar, R. C., Zhao, J., Wenger, L., & Kral, A. H. (2020). Opioid Withdrawal symptoms, frequency, and pain characteristics as correlates of health risk among people who inject drugs. Drug and alcohol dependence, 211, 107932. https://doi.org/10.1016/j.drugalcdep.2020.107932 Center for Drug Evaluation and Research. (2024). Information about Medications for Opioid Use Disorder (MOUD). FDA. https://www.fda.gov/drugs/information-drug-class/information-about-medications-opioid-use-disorder-moud Centers for Disease Control and Prevention. (n.d.). Preventing opioid use disorder. U.S. Department of Health and Human Services. Retrieved January 28, 2025, from https://www.cdc.gov/overdose-prevention/prevention/preventing-opioid-use-disorder.htmlOpioids: What They Are, Side Effects & Disorders. (n.d.). Cleveland Clinic. Retrieved January 28, 2025, from https://my.clevelandclinic.org/health/drugs/21127-opioids
