Effects of Chronic Morphine Administration on Cytokine & Chemokine Protein and Gene Expression

Abstract

Chemokine and chemokine receptors play a major role in HIV-1 infectivity, and their expression can be modulated by opioid drugs of abuse, further implicating a role for these drugs in altering HIV-1 susceptibility. Several of the opioid agonists including morphine and heroin impair resistance to a variety of infectious agents including HIV-1 by modulating both innate and acquired immune responses. The aim of my thesis is to understand whether chronic morphine administration alters the expression of pro-inflammatory cytokines and chemokines. Since there are limited reports in the literature describing the effects of chronic opioid administration on immune competence, a macaque model was devised to analyze the immune system following chronic morphine administration. My results show that animals receiving morphine exhibit enhanced proinflammatory CXCL8 protein expression in response to stimulation with various Toll Receptor (TLR) ligands. This result was observed in responses to either the combination of LPS and IFNγ, or with the TLR ligand peptidoglycan. These results suggest that chronic morphine administration increases immune system responsiveness. We extended these studies on opioid-induced signaling and gene expression in human subjects and observed that opioid treatment induces the expression of CXCL10, TLR4, and the aryl hydrocarbon receptor (AHR) in leukocytes early in response to treatment. In sum, I have shown that opioid agonists modulate important immune-response genes, and these genes are important for the generation of antimicrobial immunity.