Lucia Barrenechea
Research Mentor(s): Jessica Anand
Mentor Department: Pharmacology
Authors: Lucia Barrenechea, Dawn Jessup , Jessica P. Anand , John R. Traynor
Session: Session 3 (11:00am – 11:50am)
Presentation Type: Poster 46
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 12 years or older (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 (Bluthenthral, et al., 2020). Patients are often unwilling to engage in harm-reduction strategies due to these aversive symptoms, which results in significantly increased chances of relapse. Many of these withdrawal effects have been suggested to be mediated by the Kappa Opioid Receptor (KOR). We hypothesized that the use of opioid-positive allosteric modulators (PAMs) would prove beneficial in circumventing opioid withdrawal effects mediated through KOR signaling. To test this we utilized 6 novel compounds which were structural analogs of the opioid receptor-positive allosteric modulator BMS-986122 and measured them against dynorphin A stimulation on human Kappa Opioid Receptors expressed in Chinese hamster ovary cells (CHO-hKOR), in an in-vitro radioactive binding assay utilizing GTPy35S. The effective concentration at 50% of the maximum efficacy values (EC50) was compared for differences in potencies based on the standard dynorphin A response curve in the presence or absence of the individual compounds. Each compound was assayed three times in duplicate runs (n=6), and EC50s were then averaged together. None of the novel allosteric compounds significantly shifted the EC50s concentration-response curve relative to the standard dynorphin A curve. When taken in context with data previously obtained by our group which showed these structural analogs were potent positive allosteric modulators at the mu-opioid receptor, these data suggest a possible therapeutic mechanism with which these compounds may significantly improve opioid withdrawal symptoms. Our future directions will include introducing the experimental compounds to an in-vivo assay, testing the possibility of reducing withdrawal behaviors presented in opioid-dependent animals, and assessing downstream signaling in in-vitro models of opioid dependence and withdrawal. Taken together these data suggest opioid receptor-positive allosteric modulators may be a valuable therapeutic tool for many individuals struggling with Opioid Use Withdrawl.
