Abstract
Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an interorgan, interindividual, and interspecies basis. In both species, morphine was associated with decreased levels of Ki-67(+) T-cell activation but with only minimal changes in overall T-cell counts, neutrophil counts, and NK cell counts. Although changes in T-cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent.
Highlights
From the ‡Biological Sciences Division, Pacific Northwest National Laboratories, Richland, Washington; §Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California; ¶Department of Microbiology, ʈWashington National Primate Research Center, University of Washington, Seattle, Washington
Samples were obtained from lymph node, colon, and CSF on days 0 and 20 and from peripheral blood on days 0, 10, and 20, and these samples were subjected to immunomics and proteomics analyses
In the results presented below, the global response to morphine will be discussed in the context of individual compartments, i.e. lymph node, colon, CSF, and peripheral blood
Summary
We comprehensively sampled inguinal lymph node, colon, CSF, and peripheral blood, and measured the immunomic and proteomic changes within these various biological compartments before and after the administration of morphine. Morphine treatment resulted in significant changes (p Յ 0.01) in the abundance of 689 proteins in the tissues and fluids analyzed: 422 (35%) in the lymph node, 215 (18%) in the colon, 113 (45%) in CSF, and 56 (40%) in plasma.
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