Central effects of glucocorticoid receptor antagonist RU-38486 on lipopolysaccharide and stress-induced fever

1994 ◽  
Vol 267 (3) ◽  
pp. R705-R711 ◽  
Author(s):  
J. L. McClellan ◽  
J. J. Klir ◽  
L. E. Morrow ◽  
M. J. Kluger
Keyword(s):  
Receptor Antagonist ◽  
Open Field ◽  
Intraperitoneal Injection ◽  
Plasma Corticosterone ◽  
Anterior Hypothalamus ◽  
Intracerebroventricular Injection ◽  
Type Ii ◽  
Central Effects ◽  
Lower Temperature ◽  
The Brain

Intracerebroventricular administration of the glucocorticoid type II receptor antagonist RU-38486 leads to an increased fever after injection of lipopolysaccharide (LPS) in awake unrestrained rats, indicating that endogenous glucocorticoids act centrally to lower temperature after the intraperitoneal injection of LPS. The current study examined where in the brain glucocorticoids exert these effects on fever and if these effects involve plasma interleukin-6 and corticosterone. RU-38486 injected intracerebroventricularly (10 ng/animal) led to a significantly greater rise in biotelemetered body temperature (BT) 120-240 min post-LPS (50 mg/kg ip) compared with controls (0.89 +/- 0.14 vs. 0.44 +/- 0.22 degree C, P = 0.0482), confirming our earlier study, and also led to a significantly greater rise in BT after exposure to an open field when the RU-38486 was infused intracerebroventricularly (10 ng/ml, 1 microliter/h) for 20 h before the exposure (1.48 +/- 0.18 vs. 1.06 +/- 0.11 degree C, P = 0.023). When rats were injected with RU-38486 into the anterior hypothalamus (1 ng/animal), there was an increased rise in BT after injection of LPS (1.74 +/- 0.27 vs. 0.82 +/- 0.22 degree C, P = 0.0075) but not after exposure to an open field (1 ng intrahypothalamically, 1 h preexposure). There were no differences in plasma interleukin (IL)-6-like activity or plasma corticosterone after intracerebroventricular injection of RU-38486 and intraperitoneal injection of LPS. We conclude that endogenous glucocorticoids are working centrally to modulate fever after LPS and exposure to open field, and that LPS-induced fever is modulated by glucocorticoids in the anterior hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of brain IL-1 type II receptors in fever and thermogenesis in the rat

1993 ◽  
Vol 265 (4) ◽  
pp. E585-E591 ◽  
Author(s):  
G. Luheshi ◽  
S. J. Hopkins ◽  
R. A. Lefeuvre ◽  
M. J. Dascombe ◽  
P. Ghiara ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Low Dose ◽  
Interleukin 1 ◽  
Type I ◽  
Intracerebroventricular Injection ◽  
Type Ii ◽  
Central Effects ◽  
Conscious Rats ◽  
Central Actions ◽  
The Brain

Interleukin-1 (IL-1) acts centrally to induce fever and thermogenesis in rodents. The central actions of IL-1 alpha and IL-1 beta apparently involve different mechanisms, and the effects of IL-1 beta are not consistent with interaction with a type I (IL-1RI) 80-kDa receptor. In the present study the involvement of the type II IL-1 receptor (IL-1RII) was tested in the rat by examining the effects of central injection of a monoclonal antibody (ALVA-42), which blocks the IL-1RII. Pretreatment of rats with ALVA-42 (6 micrograms icv) inhibited the thermogenic and pyrogenic responses to intracerebroventricular injection of 5 ng (but not 50 ng) of IL-1 beta in conscious rats but did not significantly modify responses to IL-1 alpha. ALVA-42 also failed to modify the responses to peripherally administered IL-1 beta (1 microgram) but significantly attenuated the pyrogenic and thermogenic responses to peripheral (125 micrograms) or central (1 microgram) injection of endotoxin. These data indicate that IL-1RII mediates the central effects of a low dose of IL-1 beta, but not IL-1 alpha, on fever and thermogenesis in the rat. They also imply that responses to endotoxin are due, at least in part, to the activation of IL-1RII by IL-1 beta released within the brain and that effects of peripherally injected IL-1 beta involve different mechanisms, probably associated with IL-1RI.

Vasopressin enhances the clearance of β-endorphin immunoreactivity from rat cerebrospinal fluid

1990 ◽  
Vol 122 (2) ◽  
pp. 191-200 ◽  
Author(s):  
C. G. J. Sweep ◽  
Margreet D. Boomkamp ◽  
István Barna ◽  
A. Willeke Logtenberg ◽  
Victor M. Wiegant
Keyword(s):  
Cerebrospinal Fluid ◽  
Receptor Antagonist ◽  
Short Duration ◽  
Lateral Ventricle ◽  
Underlying Mechanism ◽  
Terminal Phase ◽  
Intracerebroventricular Injection ◽  
Intracerebroventricular Administration ◽  
Biphasic Pattern ◽  
The Brain

Abstract The effect of intracerebroventricular (lateral ventricle) administration of arginine8-vasopressin (AVP) on the concentration of β-endorphin immunoreactivity in the cerebrospinal fluid obtained from the cisterna magna was studied in rats. A decrease was observed 5 min following injection of 0.9 fmol AVP. No statistically significant changes were found 5 min after intracerebroventricular treatment of rats with 0.09 or 9 fmol. The decrease induced by 0.9 fmol AVP was of short duration and was found 5 min after treatment but not 10 and 20 min. Desglycinamide9-AVP (0.97 fmol), [pGlu4, Cyt6]-AVP-(4–9) (1.44 fmol), Nα-acetyl-AVP (0.88 fmol), lysine8-vasopressin (0.94 fmol) and oxytocin (1 fmol) when intracerebroventricularly injected did not affect the levels of β-endorphin immunoreactivity in the cerebrospinal fluid 5 min later. This suggests that the intact AVP-(1–9) molecule is required for this effect. Intracerebroventricular pretreatment of rats with the vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP (8.63 fmol) completely blocked the effect of AVP (0.9 fmol). In order to investigate further the underlying mechanism, the effect of AVP on the disappearance from the cerebrospinal fluid of exogenously applied β-endorphin was determined. Following intracerebroventricular injection of 1.46 pmol camel β-endorphin-(1–31), the β-endorphin immunoreactivity levels in the cisternal cerebrospinal fluid increased rapidly, and reached peak values at 10 min. The disappearance of β-endorphin immunoreactivity from the cerebrospinal fluid then followed a biphasic pattern with calculated half-lifes of 28 and 131 min for the initial and the terminal phase, respectively. Treatment of rats with AVP (0.9 fmol; icv) during either phase (10, 30, 55 min following intracerebroventricular administration of 1.46 pmol β-endorphin-(1–31)) significantly enhanced the disappearance of β-endorphin immunoreactivity from the cerebrospinal fluid. The data suggest that vasopressin plays a role in the regulation of β-endorphin levels in the cerebrospinal fluid by modulating clearance mechanisms via V1-receptors in the brain.

Central effects of morphine and morphine-6-glucuronide on tissue protein synthesis

1996 ◽  
Vol 271 (3) ◽  
pp. R619-R625 ◽  
Author(s):  
Y. Hashiguchi ◽  
P. E. Molina ◽  
V. R. Preedy ◽  
P. H. Sugden ◽  
M. A. McNurlan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Fold Increase ◽  
Potential Contribution ◽  
Intracerebroventricular Injection ◽  
Plasma Epinephrine ◽  
Tissue Protein ◽  
Central Effects ◽  
Arterial Ph ◽  
Tissue Protein Synthesis ◽  
The Brain

The central and peripheral effects of morphine sulfate (Mor) and morphine-6-glucuronide (M6G) on the fractional rates of tissue protein synthesis (kappa s) were determined. We determined ks in conscious rats 2 h after intracerebroventricular injection of Mor (80 micrograms/rat), M6G (1 microgram/rat), or H2O (5 microliters). Intracerebroventricular Mor and M6G administration decreased ks in the liver by 19 and 18% spleen by 19 and 17%, and gastrocnemius by 18 and 17%, respectively. Intravenous injection of Mor (8 mg/kg) or M6G (0.4 mg/kg) did not affect ks in any of the tissues studied. Intracerebroventricular Mor and M6G resulted in an equivalent 10- to 15-fold increase in plasma epinephrine, 2- to 3-fold increase in norepinephrine, and 80-90% increase in corticosterone, with no change in insulin levels. Intracerebroventricular Mor produced a significant 30% decrease in arterial partial O2 pressure (PaO2) and no significant changes in arterial pH and arterial partial CO2 pressure (PacO2). Intracerebroventricular M6G decreased PaO2 (40%) and pH (from 7.44 +/- 0.01 to 7.34 +/- 0.02) and increased Paco2 (36%). The potential contribution of hypoxia to the opiate-induced decrease in ks was assessed in an additional set of rats exposed to 5% O2-95% N2. One or 2 h of hypoxia decreased protein synthesis in the brain by 47 and 56%, liver by 69 and 69%, and skeletal muscle by 51 and 52%, respectively. Our results indicate that Mor and M6G suppress tissue protein synthesis through central mechanisms, most likely mediated by opiate-induced respiratory depression in association with neural and hormonal alterations.

scholarly journals Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.

1991 ◽  
Vol 173 (4) ◽  
pp. 931-939 ◽  
Author(s):  
K W McIntyre ◽  
G J Stepan ◽  
K D Kolinsky ◽  
W R Benjamin ◽  
J M Plocinski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Receptor Antagonist ◽  
Intraperitoneal Injection ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Ic50 Values

Recombinant human interleukin 1 receptor antagonist (IL-1ra) and 35F5, a neutralizing monoclonal antibody (mAb) to the type I mouse IL-1 receptor, were examined for their ability to bind to IL-1 receptors (IL-1Rs) on various types of mouse cells and to block immune and inflammatory responses to IL-1 in vitro and in mice. IL-1ra competed for binding of 125I-IL-1 alpha to type I IL-1R present on EL-4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1 alpha. In contrast, IL-1ra bound with very low affinity (IC50 values ranging from 10 to 200 micrograms/ml) to cells expressing type II IL-1R, i.e., 70Z/3 pre-B cell line and polymorphonuclear leukocytes (PMN) derived from bone marrow and acute inflammatory exudates. The mAb 35F5 bound specifically to type I IL-1R; no inhibition of 125I-IL-1 alpha binding to cells having type II IL-1R was observed with very high concentrations of antibody. While neither IL-1ra nor 35F5 had intrinsic activity in bioassays using T helper D10.G4.1 cells and mouse thymocytes, both agents blocked the ability of IL-1 to stimulate proliferation of these cells. The effects of IL-1ra and 35F5 on acute inflammatory responses in mice were also evaluated. IL-1ra and 35F5 blocked the local accumulation of PMN after intraperitoneal injection of rIL-1 alpha. The response to IL-1 was inhibited when IL-1ra or 35F5 was administered simultaneously with or before administration of IL-1. IL-1ra and 35F5 also blocked PMN accumulation after intraperitoneal injection of lipopolysaccharide or proteose peptone, suggesting IL-1 is important in mediating responses to these agents. In addition, IL-1ra and 35F5 significantly blocked the ability of IL-1 to stimulate egress of PMN from bone marrow, to induce a transient neutrophilia, and to elevate serum levels of hepatic acute phase proteins, IL-6, and corticosterone. Thus, IL-1ra and 35F5 competitively inhibit the binding of IL-1 to the IL-1R on certain cell types. These two IL-1 receptor antagonists act to inhibit biological responses induced by IL-1 and other inflammatory agents.

Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat

1996 ◽  
Vol 270 (1) ◽  
pp. E91-E95 ◽  
Author(s):  
G. Luheshi ◽  
A. J. Miller ◽  
S. Brouwer ◽  
M. J. Dascombe ◽  
N. J. Rothwell ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Receptor Antagonist ◽  
Interleukin 6 ◽  
Single Injection ◽  
Interleukin 1 ◽  
Intracerebroventricular Injection ◽  
Febrile Response ◽  
Interleukin 1 Receptor Antagonist ◽  
The Brain ◽  
Pyrogenic Activity

Although a number of studies indicate that the pyrogenic activity of lipopolysaccharide (LPS) and/or interleukin (IL)-1 is mediated via induction of IL-6, this has been questioned by recent evidence demonstrating a dissociation between fever and circulating IL-6. The present study reexamines this relationship by use of human recombinant interleukin-1 receptor antagonist (IL-1ra). Injection of LPS (100 micrograms/kg ip) into rats induced fever (2.0 degrees C) that was significantly inhibited (P < 0.05) when IL-1ra (16 mg/kg ip) was given 1 and 2 h after LPS. The rise in plasma IL-6 preceded the febrile response by 1-1.5 h and, although the concentrations of bioactive IL-6 in plasma and cerebrospinal fluid (CSF) were not reduced at 4 h, at 2 h plasma and CSF IL-6 bioactivity was inhibited by 80 and 70%, respectively, after a single injection of IL-1ra (16 mg/kg ip). Intracerebroventricular injection of IL-1ra (200 micrograms/rat) inhibited LPS fever but did not affect the plasma IL-6 bioactivity measured 2 or 4 h after intraperitoneal LPS. These data show that peripheral IL-1 plays a part in the induction of both fever and the rise in plasma IL-6 that precedes it, and that IL-1 within the brain is also important in the induction of fever by LPS.

The CNS site of glucocorticoid negative feedback during LPS- and psychological stress-induced fevers

1996 ◽  
Vol 271 (3) ◽  
pp. R732-R737 ◽  
Author(s):  
L. E. Morrow ◽  
J. L. McClellan ◽  
J. J. Klir ◽  
M. J. Kluger
Keyword(s):  
Glucocorticoid Receptor ◽  
Dentate Gyrus ◽  
Receptor Antagonist ◽  
Open Field ◽  
Psychological Stress ◽  
Negative Feedback ◽  
Brain Regions ◽  
Type Ii ◽  
Neural Connections ◽  
Sites Of Action

Glucocorticoids exert negative feedback in the anterior hypothalamus (AH) during lipopolysaccharide (LPS)-induced fevers, but the central location of their negative feedback during psychological stress-induced fever has not been determined. To confirm that glucocorticoid modulation of LPS fever occurs in the AH, adrenalectomized animals were injected intrahypothalamically with either 0.25 ng of corticosterone or vehicle followed by 50 micrograms/kg LPS intraperitoneally. Animals pretreated with corticosterone developed significantly smaller fevers (P = 0.007) than animals given vehicle. To determine if glucocorticoid modulation during psychological stress-induced fever may occur in the hippocampus, the fornix was transected to block hippocampal communication with the AH. This resulted in significantly larger psychological stress-induced fevers (P = 0.02) compared with sham-operated animals. There were no differences between these groups for LPS-induced fevers (P = 0.92). To determine where in the hippocampus glucocorticoids might exert their negative feedback during psychological stress, rats were microinjected with either 1 ng RU-38486 (a type II glucocorticoid receptor antagonist) or vehicle into the dentate gyrus prior to exposure to the open field. There were no differences between the psychological stress-induced fevers of the RU-38486- and vehicle-injected groups, supporting the hypothesis that these fevers are modulated elsewhere in the hippocampus. Our data support the hypothesis that glucocorticoids modulate LPS-induced fever in the AH and do not involve the hippocampus, and that psychological stress-induced fevers are modulated by neural connections between the hippocampus and the hypothalamus. The precise sites of action of glucocorticoid negative feedback on stress-induced fevers in the hippocampus (or other brain regions) are not yet known.

Neuroimaging in Drug Discovery and Development: Paradigms for Accelerating New Drug Availability

2001 ◽  
Vol 14 (5) ◽  
pp. 407-415
Author(s):  
John T. Metz ◽  
Malcolm D. Cooper ◽  
Terry F. Brown ◽  
Leann H. Kinnunen ◽  
Declan J. Cooper
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
New Drugs ◽  
Central Effects ◽  
Drug Discovery And Development ◽  
Psychological Tasks ◽  
The Brain ◽  
Phase Iv

The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).

scholarly journals Interleukin-1 receptor antagonist binds to the type II interleukin-1 receptor on B cells and neutrophils.

1991 ◽  
Vol 266 (30) ◽  
pp. 20311-20315 ◽  
Author(s):  
D.J. Dripps ◽  
E. Verderber ◽  
R.K. Ng ◽  
R.C. Thompson ◽  
S.P. Eisenberg
Keyword(s):  
B Cells ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Type Ii ◽  
Interleukin 1 Receptor Antagonist

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

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