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Biomedical subjects

R D Brown

Publications and source records attributed to R D Brown.

At least 163 records · Page 9Linked to original sources
PubMed1994

Immunotoxicity of nitrobenzene in female B6C3F1 mice.

Nitrobenzene (NBZ) is primarily employed as an oxidizing agent in the synthesis of analine and benzene compounds. It produces myelotoxic effects and effects on erythrocytes in both animal models and man. Reported hepatosplenomegaly and effects on the bone marrow are indicators that NBZ may be immunotoxic. In these studies, female B6C3F1 mice were exposed to 30, 100 and 300 mg/kg of NBZ in corn oil by gavage for 14 consecutive days. To assess the immunotoxic potential of NBZ, body and organ weights were determined and selected immunologic and host resistance responses were studied. In these studies, the liver and spleen appeared to be the primary target organs. Both liver and spleen weights were dose dependently increased. Gross histopathologic examinations revealed significant changes in the spleen, consisting of severe congestion of the red pulp areas with erythrocytes and reticulocytes. Serum chemistry profiles showed increases in alanine aminotransferase and aspartate aminotransferase activities, indicating liver toxicity. Hematologic studies showed a decrease in erythrocyte number and a concomitant increase in mean corpuscular hemoglobin and mean corpuscular volume. A dose-dependent increase in peripheral reticulocytes was also seen. DNA synthesis was enhanced, as was the number of formed elements and the number of monocyte/granulocyte stem cells in the bone marrow of treated mice. IgM responses were decreased and the phagocytic activity of macrophages in the liver was dose dependently increased with a concomitant decrease in the activities in the spleen and lung. Other immunological parameters examined were unchanged. Host resistance to microbial or viral infection was not markedly altered by NBZ; however, there were trends towards increased susceptibility where T-cell function contributes to host defense. These data indicate that NBZ-induced hemolysis and liver injury are linked to the observed alterations in bone marrow activity.

Administration, Oral↗
PubMed1994

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: I. Para-nitrotoluene.

para-Nitrotoluene (p-nitrotoluene) is used primarily as an intermediate in the production of various dyes, explosives, pharmaceuticals, and in the production of rubber and agricultural products. Previous investigations indicated that p-nitrotoluene was mutagenic in the Ames Test and that other mono-substituted nitrotoluenes bound covalently to hepatic macromolecules. The objective of these studies was to evaluate the potential immunotoxicity of p-nitrotoluene in mice exposed by the oral route. Mice exposed to p-nitrotoluene (200-600 mg/kg) daily for 14 days showed modest dose-dependent increases in liver and spleen weights. The livers of mice exposed subchronically to 400 and 600 mg/kg showed a mild to moderate swelling of the hepatocytes adjacent to the central veins; this swelling appeared to be reversible and there was no evidence of necrosis. The proportion of monocytes in blood was decreased in mice treated with p-nitrotoluene or toluene. Serum chemistries, bone marrow cellularity and the number of CFU-M and CFU-GM were unaffected. Immunologic investigations showed p-nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a 24% decrease in the percentage of CD4+ T lymphocytes in the spleen. There was no dose-dependent alteration of peritoneal macrophage numbers or differential count, unstimulated natural killer cell activity, response to B cell mitogen LPS, C3 activity or interferon levels. Exposure of mice to p-nitrotoluene decreased resistance to Listeria monocytogenes but not to Streptococcus pneumoniae, Plasmodium yoelii or the B16F10 melanoma, and increased resistance to the PYB6 tumor. These studies indicated that the immune system is an important target for toxicity of p-nitrotoluene. The decreased host resistance to L. monocytogenes can be attributed to the decrease in T lymphocytes and to a decreased delayed hypersensitivity response to KLH.

Administration, Oral↗
PubMed1994

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: II. Meta-nitrotoluene.

The nitrotoluenes are chemicals used in dyes, agricultural products, pharmaceuticals and explosives. In the present studies, the toxicology and immunotoxicity of meta-nitrotoluene (m-nitrotoluene) were evaluated. Mice, exposed to m-nitrotoluene at dose levels of 200, 400 and 600 mg/kg/body weight for 2 weeks by gastric gavage, gained body weight over the treatment period to a slightly greater extent than the control groups. Of the selected organs weighed, the liver and kidney of mice exposed to m-nitrotoluene were increased in weight while the thymus weight was decreased. The liver of mice exposed to m-nitrotoluene, but not ortho-nitrotoluene, showed slight to moderate swelling of the hepatocytes adjacent to the central veins. The hepatocyte swelling appeared to be reversible and there was no evidence of necrosis. The hematology and serum chemistries examined were unaffected by m-nitrotoluene exposure although there were modest decreases in the percentage of polymorphonuclear leukocytes and eosinophils in differential blood counts. Bone marrow cellularity and the number of CFU/M and CFU/GM were unaffected by m-nitrotoluene exposure. m-Nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a slight (8%) decrease in the percentage of B lymphocytes in the spleen. The response to the T cell mitogens was suppressed by as much as 39%. Fc-mediated adherence and phagocytosis of chicken erythrocytes and NK cell activity were increased dose dependently in mice exposed to m-nitrotoluene. Several immune parameters were unaffected by exposure to m-nitrotoluene, including the IgG response to sRBC, responses to the B cell mitogen LPS and to allogeneic cells, and serum interferon levels. Resistance to Streptococcus pneumoniae and Plasmodium yoelii were unaffected also. Resistance to the tumor model PYB6 was increased. Exposure of mice to m-nitrotoluene decreased resistance to Listeria monocytogenes. The decreased resistance to L. monocytogenes may be related to an effect on T cells, evidenced by a decrease in T cell numbers and in the DHR.

Administration, Oral↗
PubMed1994

Immunotoxicity of 2,4-diaminotoluene in female B6C3F1 mice.

2,4-Diaminotoluene (DAT) has been demonstrated to be a potent carcinogen. The present studies were carried out to determine the toxic and immunotoxic potential of DAT. Mice exposed to DAT at 25-100 mg/kg per day for 14 days by gavage showed a 42% increase in liver weight and a slight decrease in spleen weight. Histopathologic evaluation of selected organs showed the liver to be the major target with morphological changes which were dose dependent. The high dose (100 mg/kg) was associated with moderate centrilobular necrosis. No abnormal structure was noted in the spleen, lungs, thymus, kidney or mesenteric lymph nodes. The liver toxicity was associated with an elevation in alanine aminotransferase activity. The only change noted in selected hematologic parameters was a 64% increase in peripheral blood leukocytes. Mice exposed to DAT showed a decreased IgM and IgG response to sheep erythrocytes. The decrease was not a function of a decreased number of B cells because the number of B cells increased dose dependently. Proliferative capacity of immunocompetent cells was not impaired by exposure to DAT as measured by the response to several mitogens. The delayed hypersensitivity response to keyhole limpet hemocyanin in mice exposed to DAT was increased. Natural killer cell activity was decreased dose dependently and may represent a spleen cell pool shift because the number of B cells increased in the presence of a decreasing spleen size. Serum C3 was suppressed at the high dose of DAT. Phagocytosis by splenic macrophages, but not peritoneal macrophages, was inhibited by DAT exposure. DAT exposure for 14 days decreased host resistance to the bacteria, Streptococcus pneumoniae and Listeria monocytogenes, while host resistance to the pulmonary tumor model, B16F10, and the PYB6 fibrosarcoma was unaffected by DAT exposure. These data indicate that DAT is hepatotoxic and perturbs the differentiation and maturation of leukocytes.

Administration, Oral↗
PubMed1994

Multiple myeloma: expression of nucleoside transporters on malignant plasma cells and their relationship to cellular proliferation.

The expression of nucleoside transporters is a limiting factor in the pharmacology of the nucleoside analogue, cytosine arabinoside (AraC) and is associated with cellular proliferation. We investigated the expression of nucleoside transporters on plasma cells from the bone marrow of 51 patients with multiple myeloma by 2-colour immunofluorescence flow cytometry, utilising 5-(SAENTA-x8)-fluorescein, a fluorescent ligand for the nucleoside transporter and anti-CD38 conjugated to phycoerythrin, as CD38 expression has unique characteristics on plasma cells. Mean nucleoside transporter expression on bone marrow plasma cells from patients with myeloma (1777 +/- 2181 transporters/plasma cell) was not significantly different from expression on plasma cells from normal bone marrow (997 +/- 1096 transporters/plasma cell). However, analysis of disease subgroups revealed a significant trend towards increased transporter expression in patients with progressive disease compared to those with stable disease (chi 2 = 4.0, p < 0.05). Nucleoside transporter expression correlated significantly with the plasma cell labeling index (LI) (r = 0.45, p < 0.01) and serum thymidine kinase levels (r = 0.66, p < 0.01), both markers of cellular proliferation but not with c-myc oncoprotein expression. These findings suggest that flow cytometric measurement of nucleoside transporter expression on plasma cells provides a rapid and convenient measurement of disease activity or quiescence in myeloma.

ADP-ribosyl Cyclase↗
PubMed1994

Prognostic factors in myeloma: what they tell us about the pathophysiology of the disease.

Prognostic factors in myeloma are not only important for allowing comparisons to be made between therapeutic protocols but they also provide us with an insight into the pathophysiology of the disease and important mechanisms which result in disease progression. Prognostic factors in myeloma relate to the inherent proliferative capacity of the malignant clone, tumor bulk, renal function and other factors which reflect tumor host and host tumor interactions. The highly significant effect of the labelling index (LI) suggests that the clonogenic cell is ontologically very close to the malignant plasma cell on which the labelling index is derived. The explanation for the important role of the beta 2-microglobulin (beta 2M) level over and above its reflection of renal function is as yet unclear. Other factors involved in prognosis such as serum cytokines (IL-2 and IL-6) and soluble IL-6 receptor levels reflect host tumor interactions. An understanding of these interactions may allow us to control the disease and prevent escape from plateau phase by biological means. This may become a viable alternative to high dose aggressive chemotherapy which up till now appears unable to eradicate the malignant clone.

Cell Division↗
PubMed1994

The oncoprotein phenotype of plasma cells from patients with multiple myeloma.

The expression of 6 different oncoproteins and 2 tumour suppressor gene products in the plasma cells of 63 bone marrow samples was used to determine a profile of the oncogenic phenotype of patients with multiple myeloma. Dual label flow cytometry after periodatelysine paraformaldehyde fixation was used to detect cell surface phenotype and intracellular protein expression simultaneously. The normal range for both the incidence and intensity of expression was determined for each protein by analysing plasma cells (high CD38 intensity) in 22 normal bone marrow samples. The percentage of myeloma patients with a greater than normal incidence of plasma cells expressing these proteins was 53% for c-myc, 28% for Rb, 28% for bcl-2, 27% for c-fos, 24% for p53 wild, 22% for p53 mutant, 13% for c-neu and 13% for pan-ras. When a panel of 8 antibodies was used, 82% of the samples (n = 28) had an increased incidence of expression by at least one oncoprotein or tumour suppressor gene product. The 5 patients with a normal incidence of expression of all 8 proteins were in plateau stage and 4 had not received chemotherapy for more than 12 months. The number of patients with an increased incidence of expression by 2 or more oncoproteins was significantly greater (X2 = 9.0; p < 0.005) in progressive disease (55%) than in stable disease (14%) but there was no specific phenotype pattern associated with progressive disease. All 6 oncoproteins and both tumour suppressor gene products had a greater incidence and intensity of expression in progressive than in stable disease. The expression of c-myc oncoprotein correlated with c-myc mRNA expression in the same samples (n = 10) but c-myc did not correlate with either the plasma cell labelling index (r = -0.15) nor serum thymidine kinase (r = 0.10). Our results suggest that there is a heterogeneous, non-systematic but almost universal presence of activated oncogenes and tumour suppressor genes in the plasma cells of patients with multiple myeloma and that disease progression is associated with the accumulation of a variety of secondary genetic changes which confer increased malignant behaviour.

Biomarkers, Tumor↗
PubMed1994

Intracranial dural arteriovenous fistulae: angiographic predictors of intracranial hemorrhage and clinical outcome in nonsurgical patients.

This long-term follow-up study of 54 patients clarifies the angiographic predictors of intracranial hemorrhage (ICH) and clinical outcome in individuals with unoperated intracranial dural arteriovenous fistulae (AVF's). All of these patients were examined at the Mayo Clinic between 1976 and 1989, and all available cerebral arteriograms were reviewed by a neuroradiologist. Follow-up information was obtained for 52 patients (96%) until death or treatment intervention, or for at least 1 year after diagnosis, with a mean follow-up period of 6.6 years. Throughout this 6.6-year follow-up period, ICH related to dural AVF occurred in five of the 52 patients, for a crude risk of hemorrhage of 1.6% per year. The risk of hemorrhage at the time of mean follow-up examination was 1.8% per year. Angiographic examination revealed several characteristics that were considered potential predictors of ICH during the follow-up period. Lesions of the petrosal sinus and straight sinus had a higher propensity to bleed, although the small numbers in the series precluded a definite conclusion. A person suffering from a dural AVF with a venous varix on a draining vein had an increased risk of hemorrhage, whereas no hemorrhage was seen in the 20 patients without a varix (p < 0.05). Lesions draining into leptomeningeal veins had an increased occurrence of hemorrhage, although this increased risk was not statistically significant. Patients' initial symptoms were compared to those at follow-up evaluation. Pulsatile tinnitus improved in more than half of the 52 patients, and resolved in 75% of those showing some improvement. Individuals without a sinus or venous outflow occlusion at initial cerebral angiography were more likely to improve or remain stable (89%), whereas patients with an occlusion showed infrequent improvement (11%; p < 0.05).

Adult↗
PubMed1993

A unified view of relaxation in protein solutions and tissue, including hydration and magnetization transfer.

Protein in water solution increases magnetic relaxation rates of solvent nuclei to an extent that depends on magnetic field strength and molecular weight. Koenig and Schillinger (J. Biol. Chem. 244, 3283 (1969)) showed that a small fraction of the water molecules in the first hydration shell, bound irrotationally with a residence lifetime in the range 0.1 to 10 microseconds, would account for the phenomena. No experiments, as yet, have proven the existence of such long-lived waters, nor yielded a value for their lifetime. Analogous measurements on solutions of both denatured and cross-linked protein give data different from that of native protein, but much like results for tissue. By comparing proton and deuteron relaxation rates in solutions of native and cross-linked protein, it is possible to demonstrate the existence of these relatively long-lived waters; the data indicate that 1% of a monolayer of the waters of hydration of protein have lifetimes that cluster near 1 microsecond and, it is argued, are held in place by multiple hydrogen bonds. Assigning shorter lifetimes for waters held by fewer bonds, it is possible to develop a unified view of relaxation of water nuclei in protein solutions and in tissue, and to relate it to recent crystallographic data on hydrated protein.

Humans↗
PubMed1993

Magnetization transfer in cross-linked bovine serum albumin solutions at 200 MHz: a model for tissue.

We report results for proton 1/T1, 1/T2, and K, the rate of magnetization transfer from solvent to solute, for 5 and 10 wt. % solutions of bovine serum albumin, both native and chemically cross-linked, in undeuterated and approximately 50% deuterated water, at 4.7 T (200.1 MHz) and 19 degrees C. At this field, although K > 1/T1 for the cross-linked samples, magnetization transfer contributes little to 1/T1 directly. Therefore K was measured using off-resonance irradiation of the protein protons. The data for all the samples can be fit using a theoretical model for magnetization transfer, with three parameters: the intrinsic longitudinal relaxation rates of solute and solvent protons, and K. The magnitude of K is so large that the newly-identified, long-lived (approximately 1 microseconds) hydration sites (S.H. Koenig, R.D. Brown III, and R. Ugolini, Magn. Reson. Med., 29, 77 (1993)) must be invoked to account for K, as is necessary to explain the differential effects of cross linking on the magnetic field dependence of 1/T1 of protons and deuterons and the large 1/T1 and 1/T2 values below approximately 20 MHz in immobilized systems. Although these sites are few in number, their long resident lifetime becomes the correlation time for magnetization transfer when protein is immobilized, accounting for the large value of K. Recent data from several laboratories have shown that cross-linked protein, as used here, is a good model for 1/T1 and 1/T2 of tissue, as a function of temperature and magnetic field.

Cross-Linking Reagents↗
PubMed1993

A molecular theory of relaxation and magnetization transfer: application to cross-linked BSA, a model for tissue.

Homogeneous soft tissue, as regards its magnetic relaxation properties, is well-modeled by solutions of cross-linked protein (see Koenig and Brown, Prog. NMR Spectr. 22, 487 (1991)). Interactions at the solute-solvent interface alter the hydrodynamics of solvent water, and also couple the solute and solvent proton Zeeman energy reservoirs, giving hydrodynamic and cross-relaxation contributions to water proton relaxation that respond differently to deuteration of solvent. We report measurements of the magnetic field dependence of 1/T1 of water protons in cross-linked bovine serum albumin (BSA), for partially deuterated solvent and, in order to separate these two contributions, of 1/T1 of deuterons. The major experimental finding is that, in addition to recently identified water-binding sites on protein (covering approximately 0.2% of the surface) with water lifetimes of about 1 microsecond, there is another group of sites with lifetimes of about 23 ns, covering approximately 2% of the surface, which are evident in both proton and deuteron data. In addition, we have formulated a theory of interfacial proton-proton magnetic interactions which--with these four parameters, plus two that quantify the protein-water coupling at each site--can account for all the proton and deuteron data, in both native and cross-linked BSA.

Cross-Linking Reagents↗
PubMed1993

Fatty acids may regulate aldosterone secretion and mediate some of insulin's effects on blood pressure.

Experiments in vitro and observation made in humans suggest that some unesterified fatty acids (FA) participate, as inhibitors, in the regulation of aldosterone secretion. Removal of FA from adrenal glomerulosa cells with albumin increases the responses to angiotensin II (AII) and dibutyryl cyclic AMP. Micromolar concentrations of some FA including arachidonic, oleic, linoleic, eicosapentaenoic, and docosahexaenoic inhibit aldosterone secretion by adrenal glomerulosa cells. Inhibition is specific--some acids like stearic are inactive, and the adrenal fasciculata is relatively resistant to inhibition. Oleic acid rapidly and reversibly inhibits aldosterone secretion by perfused dog adrenals. Observations in vivo suggest a reciprocal relationship between plasma levels of FA and aldosterone: insulin infusion into dogs lowers plasma FA and increases adrenal responsiveness to All; salt infusions into humans increase plasma FA as aldosterone falls; plasma FA are low in low-renin essential hypertension where adrenal responsiveness to All is high; plasma FA are inversely correlated with ratios of aldosterone to renin in black hypertensives; and plasma FA are high in some seriously ill patients whose aldosterone levels are inexplicably low. All receptors and the final step of aldosterone biosynthesis, oxidation at the 18 position, are the adrenal sites most sensitive to FA. Insulin's antinatriuresis may be mediated in part by its ability to lower plasma FA and thereby enhance adrenal response to secretagogues.

Aldosterone↗
PubMed1993

Intermolecular protein interactions in solutions of bovine lens beta L-crystallin. Results from 1/T1 nuclear magnetic relaxation dispersion profiles.

We report the magnetic field dependence of 1/T1 of solvent water protons and deuterons (nuclear magnetic relaxation dispersion, or NMRD, profiles) for solutions of steer lens beta L-crystallin. Such data allow the study of intermolecular protein interactions over a wide concentration range, here 1-34% vol/vol, by providing a measure of the rotational relaxation time of solute macromolecules. We conclude that, for approximately less than 5% protein, the solute particles are noncompact, with a rotationally averaged volume approximately three times that of a compact 60-kD sphere. (Earlier results for alpha-crystallin, approximately 1,000 kD, from optical and osmotic measurements (Vérétout and Tardieu, 1989. J. Mol. Biol. 205:713-728), show a similar, approximately twofold, effect). At intermediate concentrations, to approximately 20% protein, there is evidence for limited association or oligomerization, as found for the structurally related gamma II-crystallin (Koenig et al. 1990. Biophys. J. 57:461-469), to a limiting size about two-thirds that of alpha-crystallin. The difference in NMRD behavior of the three classes of crystallins is consonant with their differing osmotic properties (Vérétout and Tardieu. J. Mol. Biol. 1989, 205:713-728; Kenworthy, McIntosh, and Magid. Biophys. J. 1992. 61:A477; Tardieu et al. 1992. Eur. Biophys. J. 21:1-12). We indicate how the unusual structures and interactions of these three classes of proteins can be combined to optimize transparency and minimize colloid osmotic difficulties in eye lens.

Animals↗
PubMed1993

Ki-67 and proliferating cell nuclear antigen tumor proliferative indices in DNA diploid colorectal adenocarcinomas. Correlation with histopathologic characteristics and cell cycle analysis with two-color DNA flow cytometry.

The prognostic significance of tumor proliferative activity (TPA) in colorectal adenocarcinomas (CA) determined by proliferating cell nuclear antigen (PCNA) and Ki-67 staining is not well defined. Previous investigations of TPA using Ki-67 immunohistologic studies and flow cytometric (FCM) analysis have found no correlation with conventional histopathologic parameters. To better define the relationship of these various TPA measurements in CA, the authors selected 46 tumors with diploid DNA content previously analyzed by two-color DNA FCM analysis of fresh specimens to more effectively assess actual S-phase fractions (SPFs) from cytokeratin-gated DNA histograms for comparison with the following: (1) immunohistologic Ki-67 and PCNA tumor proliferation indices (TPIs); and (2) conventional histopathologic observations of prognostic import. These data show no significant correlation coefficient between Ki-67 or PCNA TPIs and SPFs derived from FCM analysis; however, the DNA diploid tumor subset categorized as having a greater than median SPF value had a significantly higher mean Ki-67 but not PCNA proliferation index. There was no correlation of any measure of proliferation with any of the eight histopathologic features of known prognostic significance.

Adenocarcinoma↗
PubMed1993

Serum thymidine kinase as a prognostic indicator for patients with multiple myeloma: results from the MRC (UK) V trial.

The significance of serum thymidine kinase (STK) as a prognostic indicator for patients with myeloma has been evaluated by determining the pre-treatment level of STK in a retrospective study of 547 patients from the Medical Research Council (MRC) V Myeloma Trial. Overall, STK was a highly significant prognostic factor (Chi 2 = 7.91; P = 0.005). At the time of censor, 23.4% of patients with a presentation STK of < 6 U/l but only 7.9% of the patients with an STK of > 11 U/l were still alive. STK proved to be a highly significant prognostic indicator for the 270 melphalan-treated patients (Chi 2 = 12.37; P = 0.0004) but had no prognostic significance for the 277 ABCM (adriamycin, BCNU, cyclophosphamide and melphalan) treated patients (Chi 2 = 0.29; P = 0.59). When the STK data was stratified for serum B-2-microglobulin (SB2M) it was demonstrated that STK was independent of SB2M and provided additional prognostic information for patients who were treated with melphalan. Thus patients with both a low STK and SB2M had the best prognosis (median survival 1677 d) and those patients with a high STK and SB2M had the worst prognosis (median survival 519 d). STK is a good prognostic marker for patients treated with melphalan but the prognostic significance of STK may disappear with the introduction of new chemotherapy regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

C-reactive protein (CRP) levels do not reflect disease status in patients with multiple myeloma.

It has recently been suggested that a combination of C-Reactive Protein (CRP) and beta-2-microglobulin (beta 2M) can be used to devise a simple prognostic model for patients with multiple myeloma. In this study we have measured serum beta 2M, CRP and thymidine kinase (STK) in a series of 215 samples to determine their value as a monitor of disease status. A longitudinal study was also performed with 6 individual patients. CRP levels did not correlate with disease status. The mean of the stable (23.62 mg/L) and the progressive disease 23.64 mg/L) groups were almost identical (t = 0.003; p = NS) with ranges of < 5-150 mg/L and < 5-100 mg/L respectively. There was no correlation between CRP and STK (r = 0.11) or CRP and beta 2M (r = 0.05). In longitudinal studies, CRP did not necessarily reflect changes in disease activity. We conclude that CRP measurements are not valuable as a monitor of disease activity in patients with myeloma.

C-Reactive Protein↗
PubMed1993

Hepatic and splenic phagocytosis in female B6C3F1 mice implanted with morphine sulfate pellets.

Morphine sulfate has previously been shown to produce a dose-dependent decrease in hepatic phagocytosis when administered as 8-, 25- and 75-mg pellets implanted subcutaneously. This study was undertaken to determine the time course of suppression of hepatic and splenic phagocytosis after subcutaneous implantation of morphine sulfate pellets. Mice were implanted with either 75 mg of morphine sulfate or placebo pellets. The uptake of chromated sheep red blood cells by the liver and spleen was taken as an index of phagocytosis by resident Kupffer cells or macrophages, respectively. The results indicate that maximum suppression of hepatic phagocytosis by 67% occurred 18 hr after implantation of 75 mg of morphine sulfate. Hepatic phagocytic capacity returned to control levels within 48 hr of implantation. The initial time course of suppression of splenic phagocytosis by 41% was similar to that of the liver (maximum at 12 hr). However, splenic phagocytic capacity returned toward placebo levels over a longer period of time reaching control after 4 days after implantation. The opiate receptor antagonist, naltrexone (30-mg pellet), completely blocked the ability of morphine to suppress either hepatic or splenic phagocytosis. Corticosterone is known to increase in parallel with plasma morphine levels presumably through a hypothalamic-pituitary-adrenal axis. The glucocorticoid receptor antagonist RU 486 was used to block the actions of corticosterone and investigate its possible role in morphine sulfate-induced suppression of phagocytosis. RU 486 (200 mg/kg) completely blocked morphine sulfate's ability to suppress splenic phagocytosis. In contrast, RU 486 only partially blocked morphine-induced suppression of hepatic phagocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗