naloxone and Lymphoma

Nervous system disease in HIV infection is associated with toxic damage induced by effects from proinflammatory responses and oxidative stress, and such effects may be more prominent among opioid abusers. In these studies, the effects of activating retinoid receptor (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) and peroxisome proliferator activated receptor (PPAR) gamma, which belong to the steroid-lipid nuclear receptor family, on tumor necrosis factor (TNF)-alpha production and inducible nitric oxide synthase (iNOS) gene expression by stimulated U937 and SVG cells, respectively, were examined. Also studied were the effects of morphine on these responses. These studies showed that, in stimulated cells, the observed responses were suppressed by activation of the nuclear receptors as compared to non-stimulated control cells. Moreover, in phytohemagglutinin (PHA)-stimulated U937 cells, morphine reversed the TNF-alpha suppression that was induced by LG101305 and ciglitazone. Preliminary data in SVG cells suggest a tendency for morphine to have a similar effect on LG101305-exposed SVG cells stimulated with a combination of lipopolysaccharide (LPS) and interferon-gamma, whereas this effect was not induced when these cells were incubated with ciglitazone. Therefore, specific nuclear receptor activation may be potentially beneficial in the treatment of neurological disease associated with HIV infection and may show specific interactions with opioids. The mechanisms that underlie these effects require further study.

Topics: Astrocytes; Benzoates; Cell Line; Cell Line, Tumor; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation; Humans; Lymphoma; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phytohemagglutinins; Retinoid X Receptors; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrahydronaphthalenes; Thiazolidinediones; Tumor Necrosis Factor-alpha

As a first step in determining whether any subset of lymphocytes expresses opioid receptors, membranes prepared from mouse lymphoma cell lines were screened for [3H]naloxone binding sites. Membranes from the R1.1 cell line specifically bound [3H]naloxone. The Hill coefficient for [3H]naloxone binding was 0.93 +/- 0.18, and nonlinear regression analysis indicated that a one-site model was the best fit of the [3H[naloxone saturation binding data. Low concentrations of kappa-selective opioids, but neither mu nor delta opioids, inhibited [3H]naloxone binding. Saturation binding studies with the kappa-selective compound [3H]U69,593 revealed a single binding site with a KD value of 0.204 +/- 0.039 nM and a Bmax value of 31.7 +/- 3.1 fmol/mg of membrane protein. The Hill coefficient for [3H]U69,593 binding was 1.03 +/- 0.11, indicative of a single site. Time courses for the association and dissociation of [3H]U69,593 binding at 25 degrees C exhibited properties consistent with a single class of binding sites. Low concentrations of kappa-selective opioids, including dynorphin peptides, inhibited [3H]U69,593 binding, while high concentrations of mu opioids were needed to inhibit binding, and the delta-selective ligands were ineffective at concentrations up to 10 microM. Stereoselectivity of the binding site was demonstrated by the finding that the Ki value for (-)-pentazocine in inhibiting [3H]U69,593 binding was 25 times less than for the (+)-isomer. Based on its high affinity for U69,593, alpha-neo-endorphin, and dynorphin B, the kappa opioid binding site on R1.1 cell membranes belongs to the kappa 1b subtype. As observed with brain kappa opioid binding sites, sodium inhibited [3H]U69,593 binding to R1.1 cell membranes in a concentration-dependent manner. These data demonstrate that the murine lymphoma cell line R1.1 expresses kappa opioid binding sites that are very similar to brain kappa opioid binding sites.

Topics: Animals; Benzeneacetamides; Binding Sites; Cell Membrane; Lymphocytes; Lymphoma; Mice; Naloxone; Pyrrolidines; Receptors, Opioid; Tritium; Tumor Cells, Cultured

It is well known that the immune function can be compromised by stress. To investigate immune function in mice stressed by experimental restraint or unavoidable and opioid dependent stress, we evaluated the changes in total body weight and in organ weights (liver, spleen and thymus) of these animals, as well as the phagocytic activity of macrophages, the cytotoxicity of T cells and inhibitory effects on tumor growth and changes in T cell subset populations. At the same time we evaluated the effects of Neurotropin (NSP), a substance extracted from the inflamed skin of rabbits inoculated with the vaccinia virus and which appears to possess neuroimmunomodulating activity. The experimentally stressed group exhibited a reduction of phagocytic activity of macrophages, cytotoxicity of T cells and inhibitory effects on tumor growth. In addition there were changes in the population of T cell subsets. In those animals pretreated with NSP, the immunosuppression induced by stress was ameliorated. As compared with several agents which influence phagocytosis, neurotropin exhibited effects similar to that of agents that blocked the adrenaline receptor and an opioid antagonist rather than tranquilizer (diazepam) and a cholinergic receptor blocker. The pharmacologic effects of neurotropin support a relationship between the actions of the central nervous system and the immune system.

Topics: Animals; Atropine; Body Weight; Cytotoxicity, Immunologic; Diazepam; Female; Immune Tolerance; Killer Cells, Natural; Lymphoma; Macrophages; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Naloxone; Organ Size; Phagocytosis; Polysaccharides; Propranolol; Reference Values; Restraint, Physical; Stress, Psychological; T-Lymphocyte Subsets

The hypothesis that neuroendocrine stimulation after aversive handling can alter natural resistance was examined in the tail electroshock (TES) model, a procedure that can activate pituitary neuropeptide secretion. Immediately after a brief TES session, the resistance of DBA/2J mice was suppressed in proportion to the intensity of the shock. Initial suppression of the natural resistance was rapidly reversed in longer treatment protocols, and repeated aversive stimulation augmented the antitumor response, leaving the mice more resistant to lymphoma than unhandled animals. Corticosterone was released into the serum after all acute handling procedures, and hydrocortisone inoculation suppressed antitumor responses. However, serum corticosterone levels did not quantitatively correlate with the alterations in natural resistance. The observation that TES-induced suppression of natural resistance could be reversed by the opiate receptor antagonist naltrexone suggested that endogenous opiated released after TES stimulation were immunosuppressive.

Topics: Animals; Corticosterone; Electroshock; Handling, Psychological; Hydrocortisone; Immunity, Innate; Lymphoma; Mice; Mice, Inbred DBA; Naloxone; Naltrexone