Tolerance development to morphine-induced alterations of immune status (original) (raw)
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Differential tolerance to morphine's immunomodulatory effects following continuous administration
Drug and Alcohol Dependence, 1998
Rats were continuously infused with either morphine or saline via an osmotic minipump for 20 consecutive days. Effects on immune status were assessed on the twentieth day of the chronic administration period following a bolus injection of morphine administered 1 h prior to sacrifice. The morphine injection suppressed measures of splenic natural killer (NK) cell activity, mitogen-stimulated T-cell proliferation, and k-interferon (IFN) production in rats that received saline via the minipump. In rats that received chronic morphine via the minipump, the morphine injection also suppressed mitogen-stimulated splenocyte proliferation and k-IFN production but did not suppress NK cell activity. These data indicate that chronic morphine administration via osmotic minipumps leads to differential tolerance to the immunomodulatory effects of morphine. These findings support previous results indicating differential tolerance development within the immune system following chronic morphine administration via the drinking water.
Morphine-induced immune alterations
Cellular Immunology, 1990
The high incidence of human immunodeficiency virus (HIV) seropositivity among drug abusers prompted us to examine in an animal model the effects of morphine on aspects of the immune system that may be specifically related to HIV infection. We now report a robust, sustained elevation in the ratio of CD4+/CD8+ cells in the spleen and thymus of mice chronically treated with morphine. Since CD4+ cells have been reported to be target cells for HIV, these alterations, in concert with a marked cellular atrophy that appears to be restricted to organs of the immune system, suggest that opiates may serve as cofactors in altering the immune status of the host and thus contribute to the increased susceptibility to HIV infection and eventual development of AIDS in opiate abusers.
Morphine-induced immunomodulation is not related to serum morphine concentrations
European Journal of Pharmacology, 1988
Morphine pellets produced atrophy of the spleen and thymus and affected mitogen-induced lymphocyte proliferation in mice as characterized by marked suppression of concanavalin A-induced blastogenesis at 48 h, and mild stimulation at 120 h. Morphine blood levels in these animals indicated that changes in the immunomodulatory effects of morphine over time were not related to dramatic shifts in circulating morphine. Enclosure of the pellet in nylon mesh did not alter blood levels or morphine-induced immunomodulation.
Immunoregulatory effects of morphine on human lymphocytes
Clinical and Vaccine …, 1997
It is now well established that parenteral drug abuse is a significant risk factor for contracting human immunodeficiency virus type 1 (HIV-1) infection and subsequently developing AIDS. Earlier studies have shown that morphine can modulate various immune responses and therefore support the premise that morphine is a cofactor in susceptibility to and progression of HIV infection. Dysregulation of interferon (IFN) production, nonspecific apoptosis of T cells, and the immune response to soluble HIV gene products have been associated with potential mechanisms of pathogenesis in HIV disease. The present study was undertaken to examine the immunomodulatory role of morphine on HIV protein-induced lymphocyte proliferative responses, Sendai and Newcastle disease virus-induced alpha IFN (IFN-␣) and IFN- production by lymphocytes and fibroblast cells, respectively, and induction of apoptosis of normal lymphocytes in vitro. Our results demonstrate that HIV protein-induced human lymphocyte proliferative responses were significantly inhibited by morphine in a dose-dependent manner. Furthermore, morphine significantly inhibited both IFN-␣ and IFN- production by normal lymphocytes and fibroblasts but induced apoptosis of normal lymphocytes. Inhibition of IFN-␣ production by morphine could be reversed by the opiate receptor antagonist naloxone. This suggests that the immunomodulatory effects of morphine are mediated through the opioid receptor. These studies support a role of morphine as a cofactor in the pathogenesis of HIV infection and describe some of the possible pathologic mechanisms which underlie the immunoregulatory effects of morphine.
Journal of experimental & clinical cancer research : CR, 2005
Opioid drugs, including morphine, are largely used as pain control in cancer patients at different stages of neoplastic growth and progression. Therefore, the possible influence of these drugs on host immunity appears to be of considerable interest. We have examined in vitro the effect of morphine on the generation of human cytotoxic T lymphocytes (CTL) against HTLV-I induced T-cell leukemia cells (MT-2 line). The results show that the drug, at graded concentrations (from 3 pg/ml to 32 microg/ml), that include those detectable in treated patients, enhances CTL activity whereas natural killer cell activity was unaffected. The enhancing effect is particularly evident when morphine was present at the onset of lymphocyte/MT-2 co-culture. On the contrary, the drug was ineffective when added on the last day of co-culture, thus indicating that morphine operates during the generation phase of CTL, but not on mature CTL. Flow cytometric analysis of intracellular cytokine expression showed th...
Pavlovian conditioning of morphine-induced alterations of immune status
Journal of Neuroimmunology, 1992
The present study provides the first demonstration that alterations of immune status can be conditioned to environmental stimuli paired with morphine administration. In the first manipulation, male Lewis rats received 0, 2, 4, 8 or 16 conditioning sessions during which a subcutaneous injection of morphine (15 mg/kg) was paired with a distinctive environment. The results showed that subsequent re-exposure to the distinctive environment induced a decrease in the mitogenic responsiveness of splenic lymphocytes and a decrease in natural killer cell activity in animals which had received 2, 4, 8 and 16 conditioning sessions. In the second manipulation, using two conditioning sessions, a wider range of immune measures was assessed and control groups were included to ascertain whether the observed immune alterations were due to Pavlovian conditioning processes. The results showed that the environment which had been paired with morphine altered the mitogenic responsiveness of blood and splenic lymphocytes, decreased natural killer cell activity and decreased interleukin-2 production. In contrast, the conditioned environment did not have any effect on mitogenic responsiveness of lymphocytes derived from the mesenteric lymph nodes. Data from the control groups revealed that the compartment-specific immune alterations were the result of a Pavlovian conditioning process.
Journal of Neuroimmunology, 1995
This study deals with a novel role of morphine in the modulation of cellular responsiveness to immunostimulatory substances that, at first glance, appears to be in contrast to the well documented immunoinhibitory short-term effects of opiate alkaloids on cells simultaneously exposed to stimulatory molecules. Vertebrate and invertebrate immunocytes pre-exposed to morphine (10m6 M) in vitro for at least 24 h prior to the administration of lipopolysaccharide (LPS; 1 .O pg/ml) or other immunoactivating substances have revealed a distinct enhancement of their responsiveness to these signals, e.g. monocytes exposed to LPS alone resulted in 21% activation, whereas the morphine pretreated level was at 40% (P < 0.01). Prolonged pretreatment with morphine of naive human monocytes had the same effect on their sensitivity to plasma from patients having undergone cardiopulmonary bypass (CPB) operations followed by a diffuse inflammatory response. These results suggest that endogenous opiates may participate, in more than one way, in re-establishing an organism's readiness to meet a new demand on its immune system. Additional support for the concept of a role of endogenous opiates in immunomodulation was obtained by the results of in vivo tests with experimentally induced stress in Mytilus. Following their stress-induced stimulation, these animals' immunocytes could be shown to become exposed for some time to a measurable rise in endogenous morphine-like material (9 pmol/ml increasing to 59). These immunocytes, like those preincubated with exogenous morphine, displayed a heightened sensitivity to stimulation by LPS (control 21.3 k 3.1% activation compared to 47.2 f 5.1) when the morphine levels dropped. The mechanism of this enhancement of responsiveness to immunostimulation following the prolonged exposure of immunocytes to morphine, and its relationship with the known short-term immunoinhibitory opiate effects on the immune system, remains to be ascertained.
1996
Opiates and opioid agents are known to affect the immune system. In humans this includes alterations in natural killer (NK) cell activity. Morphine is reported to reduce in vivo spleen NK activity in rats, whereas for methadone only in vitro data have been described. In the present paper we describe a systematic study on the chronic effects of well-known opiates, comparing for the first.time the effects of morphine and methadone on NK cell activity in various organs: in addition to spleen, also in the peritoneal cavity, and lungs. In all organs the NK activity was determined using three effector : target cell ratios. Morphine and methadone given by food during 6 weeks decreased the NK cell activity in rat spleen, supporting published data on morphine. The role of the opiate receptor is discussed. However, the overall action of morphine could not be described as suppressive because stimulation of NK cell activity in the peritoneal cavity and lungs by morphine was found. In contrast, methadone induced a decrease in the NK cell activity in these organs. Apart from these differential expressions of morphineand methadone associated effects on NK cell activity, the findings demonstrate the potential adverse effects of these opiates on an important antiviral defence mechanism.
Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages
Life Sciences, 1993
Studies were performed to compare in vitro and in vivo effects of morphine on the phagocytic function of murine peritoneal macrophages. Macrophage monolayers were incubated with Candida albicans for 30 rain in the absence of autologous serum. Morphine added in vitro was found to decrease both the phagocytic activity (percent of phagocytic cells) and the phagocytic index (average number of ingested yeasts per cell) in a concentration-dependent manner, with maximal effects of 26% and 41%, respectively, at 10 -6 M. When morphine was administered in vivo via an implanted 75-mg pellet, there was a 22% decrease in phagocytic activity and a 40% decrease in the phagocytic index. Naltrexone completely blocked the effects of morphine both in vitro and in vivo. The results suggest that morphine is capable of interacting directly with opioid receptors on macrophages, resulting in a decrease in phagocytic function.