title: Paradoxes of immunosuppression in mouse models of withdrawal.
abstract: Previously, our laboratory showed that either abrupt (AW) or precipitated withdrawal (PW) from morphine led to profound suppression of murine splenic antibody responses to sheep red blood cells at 24 h post-withdrawal. In the present studies, we examined the immune mechanisms mediating suppression at that time point. A co-culture method was used to examine whether cells from withdrawn mice had (1) a deficit in function and/or (2) contained populations of suppressor cells. To examine the first hypothesis, cells from normal mice were co-cultured with cells from withdrawn mice in a 1:3 ratio (normal/withdrawn). To test the second hypothesis, the ratio was reversed. The results were paradoxical. Co-culture of cells in a 1:3 ratio showed that spleen cells from withdrawn mice had a deficit in macrophage function. Spleen cells from withdrawn mice also showed decreased mRNA levels of IL-1beta, IL-1-Ra, and TNF-alpha and a suppression of co-stimulatory molecule expression. To examine the second hypothesis, cells were co-cultured in a 3:1 ratio (normal/withdrawn). In this paradigm, spleen cells from abrupt withdrawn mice were shown to contain populations of both suppressor macrophages and B-cells. In vivo experiments carried out on mice 24 h post-withdrawal showed increased sensitivity to the lethal effects of LPS and increased production of TNF-alpha, implying a state of macrophage activation. Thus evidence for both suppressed and activated macrophages has been obtained in mice 24 h after abrupt withdrawal from morphine.
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Rahil T
authors.initials: RT
authors.lastname: Rahim
authors.forename: Pu
authors.initials: P
authors.lastname: Feng
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Meissler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.forename: Martin W
authors.initials: MW
authors.lastname: Adler
authors.forename: Toby K
authors.initials: TK
authors.lastname: Eisenstein
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000008:administration & dosage; D018920:Coculture Techniques / Q000379:methods; D004195:Disease Models, Animal; D004343:Drug Implants; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006462:Hemolytic Plaque Technique; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects; D009270:Naloxone / Q000008:administration & dosage / Q000009:adverse effects; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D009294:Narcotics / Q000008:administration & dosage / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013375:Substance Withdrawal Syndrome / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D004343:Drug Implants; D007378:Interleukins; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; D009294:Narcotics; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009270:Naloxone; D009020:Morphine