Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?
Marjorie C. Gondré-Lewis,
Igor Elman,
Tanya Alim,
Edwin Chapman,
Beverlyn Settles-Reaves,
Carine Galvao,
Mark S. Gold,
David Baron,
Shan Kazmi,
Eliot Gardner,
Ashim Gupta,
Catherine Dennen,
Kenneth Blum
Affiliations
Marjorie C. Gondré-Lewis
Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA
Igor Elman
Department of Psychiatry, Cambridge Health Alliance/Harvard Medical School, Cambridge, MA 02139, USA
Tanya Alim
Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC 20059, USA
Edwin Chapman
Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC 20059, USA
Beverlyn Settles-Reaves
Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA
Carine Galvao
Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA
Mark S. Gold
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
David Baron
Graduate College, Western University Health Sciences, Pomona, CA 91766, USA
Shan Kazmi
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
Eliot Gardner
Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
Ashim Gupta
Future Biologics, Lawrenceville, GA 30043, USA
Catherine Dennen
The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, USA
Kenneth Blum
Graduate College, Western University Health Sciences, Pomona, CA 91766, USA
While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis.
