Immune modulation caused by synthetic opioids during CD4+ T cell activation

Abstract

Abstract Opioids are heavily prescribed medications used to treat chronic pain. Since their additional response includes euphoria, there is an exceedingly high addiction rate that has led to a country wide epidemic of opioid misuse. Opioid effects are not limited to the nervous system, since leukocytes express opioid receptors, which are G-protein coupled receptors known as μ, δ, and κ, suggesting that natural and synthetic opioids might regulate the immune system. Based on previously published reports, we hypothesized that opioids induce distinct regulatory pathways in CD4+ T cells that results in inhibition of the immune response. CD4+ T cells are isolated by negative selection from peripheral blood mononuclear cell and opioid receptor expression is assessed on resting and activated T cells using flow cytometry. Two models of opioid exposure in vitro were developed to study the effects of opioids on CD4+ T cell activation. Cells were treated with a δ opioid receptor specific agonist (DPDPE) for 24 h before or after activation and harvested 24 h after the second treatment and stained for expression of a well characterized early T cell activation marker – CD69. Cells treated with an opioid after activation showed no major shifts in CD69 intensity, suggesting opioids had no influence on a previously activated T cell. However, CD4+ T cells treated with an opioid before activation exhibited an increase in CD69 expression, suggesting an unexpected enhancement of T cell activation. In conclusion, opioids seem to play distinct biological activities depending on the activation state of the CD4+ T cell, and may function as both immunoinhibitory and immunostimulatory agents. Future studies will identify the mechanisms by which opioids regulate immunity.