Prostaglandin formation in feline cerebral microvessels: effect of endotoxin and interleukin-1

The pathogenesis of fever involves the appearance of interleukin-1 in the circulation in response to appropriate noxae (e.g., endotoxin) and subsequent generation of prostaglandin E2 in the CNS. The present study was undertaken to determine whether the cerebral microvasculature may function as a source of the fever-producing prostaglandin E2. Microvessels, consisting predominantly of capillaries, were isolated from the cat forebrain by selective sieving and glass bead elutriation. Preparations contained enzymes for the synthesis of 6-keto-prostaglandin F1 alpha (hence prostaglandin I2), prostaglandin E2, and possibly prostaglandin F2 alpha. No prostaglandin D2 was detected, nor was evidence obtained for the formation of 6-keto-prostaglandin E1. Intact microvessels released prostaglandin E2 and 6-keto-prostaglandin F1 alpha under basal conditions, the latter compound exceeding the former by about sevenfold. Endotoxin stimulated prostaglandin E2 release without significantly altering 6-keto-prostaglandin F1 alpha release. In contrast, monocyte-derived interleukin-1 reduced the release of both compounds, while recombinant interleukin-1 was ineffective. Endotoxin stimulation is likely directed on the cleavage of substrate arachidonic acid from precursor lipids, while inhibition from monocyte-derived interleukin-1 is ascribed to the presence of an interfering substance. This substance, like endotoxin, is thought to act prior to the cyclooxygenase cascade and its identity remains to be ascertained. We conclude that the cerebral microvasculature does not lend itself to an active role in the genesis of fever by being the site at which blood-borne interleukin-1 promotes prostaglandin E2 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endotoxin fever in the newborn kitten. The role of prostaglandins and monoamines.

In 5--10 day-old kittens at thermoneutral environmental temperature cerebroventricular injections of 10 microgram serotonin or noradrenaline caused hyperthermia and hypothermia, respectively. Central injections of 20 and 200 ng prostaglandin E1 induced hyperthermia. Monophasic fever followed the cerebroventricular injections of 0.2 or 0.002 microgram E. coli endotoxin, both in thermoneutral and moderately cool environments. In kittens pretreated with para-chlorophenylalanine (PCPA) the endotoxin induced rise in body temperature was attenuated within 60 to 90 min after the endotoxin. Indomethacin pretreatment prevented the first part of the febrile response and only a slight temperature rise occurred after a long latency. Central injections of phentolamine did not modify the fever response, while centrally applied propranolol modified the fever course so that it resembled that seen in PCPA treated kittens. The central mediation of endotoxin fever in the kitten is complex, despite that the pattern of the temperature change is simple (monophasic). Arachidonic acid metabolites and serotonin of the central nervous system may be involved in the reaction, while the activation of central noradrenergic mechanisms does not seem to be indispensable for the response. The changes in mediators are similar to those in newborn guinea pigs, although the fever course is different in the two species.     

Effect of a mu-opioid receptor-selective antagonist on interleukin-6 fever

The endogenous opioid system has been found to be involved in fever caused by pyrogens. Recent work in our laboratory has demonstrated that the mu-opioid receptor is involved in interleukin-1beta (IL-1beta)- and in lipopolysaccharide (LPS)-induced fevers. In the present study, we have investigated the role of the mu-opioid receptor in the preoptic anterior hypothalamus (POAH) in fever induced by interleukin-6 (IL-6). Following stereotaxic implantation of a guide cannula into the POAH for microinjection, radio transmitters to monitor body temperature (Tb) continuously were inserted intraperitoneally. Adult male Sprague-Dawley rats were microinjected with 0.5 microg of the selective mu-opioid receptor antagonist, cyclic D-phe-Cys-Try-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), into the POAH. Thirty min later, IL-6 (100 ng) was injected into the POAH. CTAP significantly blocked the IL-6 fever. CTAP alone had no effect on Tb during the 390-min recording period. These data indicate that mu-opioid receptors within the POAH mediate IL-6 fever and add to the increasing evidence that the opioid system is involved in the pathogenesis of fever in rats.     

Anxiety-like behavior induced by IL-1beta is modulated by alpha-MSH through central melanocortin-4 receptors

The proinflammatory cytokine interleukin-1beta (IL-1beta) influences neuroendocrine activity and produces other effects, including fever and behavioral changes such as anxiety. The melanocortin neuropeptides, such as alpha-melanocyte-stimulating hormone (alpha-MSH), antagonize many actions of IL-1, including fever, anorexia and hypothalamic-pituitary-adrenal (HPA) axis activation through specific melanocortin receptors (MC-R) in the central nervous system. The objective of the present study was to establish the effect of MSH peptides on IL-1beta-induced anxiety-like behavior and the melanocortin receptors involved. We evaluated the effects of intracerebroventricular (i.c.v.) administration of IL-1beta (30 ng) and melanocortin receptor agonists: alpha-MSH, an MC3/MC4-R agonist (0.2 microg) or gamma-MSH, an MC3-R agonist (2 microg) or HS014, an MC4-R antagonist (2 microg), on an elevated plus-maze (EPM) test. Injection of IL-1beta induced an anxiogenic-like response, as indicated by reduced open arms entries and time spent on open arms. The administration of alpha-MSH reversed IL-1beta-induced anxiety with co-administration of HS014 inhibiting the effect of alpha-MSH. However, the associated treatment with gamma-MSH did not affect the anxiety response to IL-1beta. These data suggest that alpha-MSH, through central MC4-R can modulate the anxiety-like behavior induced by IL-1beta.     

Interleukin 1 reduces opioid binding in guinea pig brain

Interleukin 1 (IL1) is a macrophage-derived polypeptide which signals neurons in the preoptic-anterior hypothalamus to initiate fever and the acute-phase glycoprotein response. Recently, increases in cerebrospinal fluid and hypothalamic levels of β-endorphin have been reported during endotoxin (LPS)- and IL1-induced fevers, suggesting that this opioid may participate in the modulation of IL1 effects in the CNS. In this study, we investigated whether purified (human) IL1 influences the specific binding of three prototypic opioid agonists (2-D-alanine-5-L-methionineamide, DAME; (−)-ethylketocyclazocine, EKC; dihydromorphine, DHM) and one antagonist (naloxone) to opioid receptor-enriched membrane preparations in cerebral cortex, hypothalamus, midbrain, pons, medulla, and cerebellum of guinea pig brain. IL1 reduced the binding of these ligands to their receptors during a 30-min incubation. The extent of IL1 inhibition of a given ligand for its binding sites varied according to the brain region; within some regions, the extent of this inhibition also varied with the four ligands tested. But in cortex the effect of IL1 on the specific binding of DHM is dose-dependent. Similar results were obtained with crude homologous IL1. S. enteritidis endotoxin, suspended in pyrogen-free saline at concentrations from 4 to 36 μg/ml, did not inhibit the binding of these opioid ligands to their receptors in any brain region. These results indicate that IL1 interacts with the opiate receptors in guinea pig brain. This interaction, moreover, is not limited to the hypothalamus alone, the primary site of the pyrogenic action of IL1, but also occurs in other brain regions.     

Central endothelin ET(B) receptors mediate IL-1-dependent fever induced by preformed pyrogenic factor and corticotropin-releasing factor in the rat

Blockade of central endothelin ET(B) receptors inhibits fever induced by LPS in conscious rats. The contribution of ET(B) receptor-mediated mechanisms to fever triggered by intracerebroventricular IL-6, PGE2, PGF(2alpha), corticotropin-releasing factor (CRF), and preformed pyrogenic factor derived from LPS-stimulated macrophages (PFPF) was examined. The influence of natural IL-1 receptor antagonist or soluble TNF receptor I on endothelin (ET)-1-induced fever was also assessed. The selective ET(B) receptor antagonist BQ-788 (3 pmol icv) abolished fever induced by intracerebroventricular ET-1 (1 pmol) or PFPF (200 ng) and reduced that caused by ICV CRF (1 nmol) but not by IL-6 (14.6 pmol), PGE2 (1.4 nmol), or PGF(2alpha) (2 nmol). CRF-induced fever was also attenuated by bosentan (dual ET(A)/ET(B) receptor antagonist; 10 mg/kg iv) but unaffected by BQ-123 (selective ET(A) receptor antagonist; 3 pmol icv). alpha-Helical CRF(9-41) (dual CRF1/CRF2 receptor antagonist; 6.5 nmol icv) attenuated fever induced by CRF but not by ET-1. Human IL-1 receptor antagonist (9.1 pmol) markedly reduced fever to IL-1beta (180 fmol) or ET-1 and attenuated that caused by PFPF or CRF. Murine soluble TNF receptor I (23.8 pmol) reduced fever to TNF-alpha (14.7 pmol) but not to ET-1. The results of the present study suggest that PFPF and CRF recruit the brain ET system to cause ET(B) receptor-mediated IL-1-dependent fever.     

Effect of number of receptors for gonadotropin-releasing hormone on the release of luteinizing hormone

The relationship between number of receptors for gonadotropin-releasing hormone (GnRH) and the ability of the anterior pituitary gland to release luteinizing hormone (LH) was examined in ovariectomized ewes. A GnRH antagonist was used to regulate the number of available receptors. The dose of GnRH antagonist required to saturate approximately 50 and 90% of GnRH receptors in ovariectomized ewes was determined. Thirty min after intracarotid infusion of GnRH antagonist, ewes were killed and the number of unsaturated (i.e., those available for binding) pituitary GnRH receptors was quantified. Infusion of 10 and 150 micrograms GnRH antagonist over a 5-min period reduced binding of the labeled ligand to approximately 50 and 12% of controls, respectively. The effect of reducing the number of GnRH receptors on release of LH after varying doses of the GnRH agonist, D-Ala6-GnRH-Pro9-ethylamide (D-Ala6-GnRH) was then evaluated. One of four doses of D-Ala6-GnRH (0.125, 2.5, 50 and 400 micrograms) was given i.v. to 48 ovariectomized ewes whose GnRH receptors had not been changed or were reduced to approximately 50 or 12% of control ewes. In ewes with a 50% reduction in GnRH receptors, total release of LH (area under response curve) was lower than that obtained for controls (P less than 0.01) at the 0.125-micrograms dose of D-Ala (6.1 +/- 0.7 cm2 vs. 13.5 +/- 0.7 cm2) but was not different at the 2.5-, 50- or 400-micrograms doses of D-Ala6-GnRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma

Summary Recent preclinical and clinical studies that have demonstrated antitumor activity of high-dose recombinant interleukin-2 (rIL-2), and animal models that demonstrated a synergistic effect of low-dose cyclophosphamide, led us to study rIL-2 (Cetus Corp., Emeryville, Calif) in a phase II clinical trial in combination with low-dose cyclophosphamide in 32 patients, 18 with malignant melanoma and 14 with renal cell carcinoma. rIL-2 was given once daily at 3×10⁶ U/m², as a 30-min infusion for 14 days in cycle I and for 2×5 days in cycles II and III respectively; if tolerated, the dose was increased to a maximum of 6×10⁶ U m^–2 day^–1; the cycles, separated by 1 week treatment-free intervals, were preceded each by a single i.v. bolus of cyclophosphamide at 350 mg/m². The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever that required dose reduction during the first cycle in one-half of the patients. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor antitumor activity. No remission was achieved in patients with renal cell carcinoma, and 15% of melanoma patients showed objective responses (partial response + minor response).     

Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects

High mobility group box 1 (HMGB1), an abundant, highly conserved cellular protein, is widely known as a nuclear DNA-binding protein. HMGB1 has been recently implicated as a proinflammatory cytokine because of its role as a late mediator of endotoxin lethality and ability to stimulate release of proinflammatory cytokines from monocytes. Production of central cytokines is a critical step in the pathway by which endotoxin and peripheral proinflammatory cytokines, including interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF), produce sickness behaviors and fever. Intracerebroventricular (ICV) administration of HMGB1 has been shown to increase TNF expression in mouse brain and induce aphagia and taste aversion. Here we show that ICV injections of HMGB1 induce fever and hypothalamic IL-1 in rats. Furthermore, we show that intrathecal administration of HMGB1 produces mechanical allodynia (lowering of the response threshold to calibrated stimuli). Finally, while endotoxin (lipopolysaccharide, LPS) administration elevates IL-1 and TNF mRNA in various brain regions, HMGB1 mRNA is unchanged. It remains possible that HMGB1 protein is released in brain in response to LPS. Nonetheless, these data suggest that HMGB1 may play a role as an endogenous pyrogen and support the concept that HMGB1 has proinflammatory characteristics within the central nervous system.     

Interleukin-1 mediates endothelin-1-induced fever and prostaglandin production in the preoptic area of rats

The intracerebroventricular injection of endothelin-1 (ET-1) induces fever and increases PG levels in the cerebrospinal fluid of rats. Likewise, the injection of IL-1 into the preoptic area (POA) of the rat hypothalamus causes both fever and increased PG production. In this study, we conducted in vivo and in vitro experiments in the rat to investigate 1) the hypothalamic region involved in ET-1-induced fever and PG biosynthesis and 2) whether hypothalamic IL-1 plays a role as a mediator of the above ET-1 activities. One hundred femtomoles of ET-1 increased body temperature when injected in the POA of conscious Wistar rats; this effect was significantly counteracted by the coinjection of 600 pmol IL-1 receptor antagonist (IL-1ra). In experiments on rat hypothalamic explants, 100 nM ET-1 caused a significant increase in PGE2 production and release from the whole hypothalamus and from the isolated POA, but not from the retrochiasmatic region, in 1-h incubations. Six nanomoles of IL-1ra or 10 nM of a cell-permeable interleukin-1 converting enzyme inhibitor completely counteracted the effect of ET-1 on PGE2 release from the POA. One hundred nanomoles ET-1 also caused a significant increase in IL-1beta immunoreactivity released into the bath solution of hypothalamic explants after 1 h of incubation, although during such time ET-1 failed to modify the gene expression of IL-1beta and other pyrogenic cytokines within the hypothalamus. In conclusion, our results show that ET-1 increases IL-1 production in the POA, and this effect appears to be correlated to ET-1-induced fever in vivo, as well as to PG production in vitro.     

Oxytocin antagonist blocks the vasodepressor but not the vasopressor effect of neurohypophysial peptides in chickens

Cockerels with permanent cannulas in the brachial artery and vein were put into isolated slings. Arterial pressure and heart rate were continuously recorded. Following habituation, tests were initiated. In each cockerel 2 nmol/kg of the tested neurohypophysial peptide (NPs) or analogue was IV injected six times at 6-min intervals. Arginine vasotocin (AVT) caused an immediate vasodepressor (VDP) effect and tachycardia. These subsided within 20–30 s and were followed by a vasopressor (VP) response and bradycardia. On repeated injections of AVT, the VDP response declined and bradycardia intensified. Arginine vasopressin (AVP), oxytocin (OT), and mesotocin (MT) had short-lasting VDP effect in the following order of potency: OT = MT > AVT > AVP. Only AVT and, more effectively, AVP, caused a VP response. The VDP effect of MT and OT declined on repeated injections. When AVT was injected after three injections of MT, it had mostly an immediate VP effect. Although the V₁ agonist is VP in chickens, at the dose used the V₁ antagonist, [d(CH₂)₅,O-Me-Tyr²]AVP, had no effect on cardiovascular responses to AVT. Pretreatment with OT antagonist, [d(CH₂)₅-O-Me-Tyr^2,Thr^4,Tyr^9,Orn⁸]VT, abolished the VDP effect of all NPs. Thus, MT had no effect on blood pressure, whereas AVP and, more effectively, AVT, had a marked immediate VP action. In chickens the VDP effect of NPs is probably mediated by an OT/MT-like receptor, wherein the peptide's ring structure, shared by AVT, OT, and MT, is important. The VP effect is mediated by a receptor only partially similar to the mammalian V₁ receptor, where arginine in position 8, shared only by AVT and AVP, is necessary for action, and the native AVT is more effective than the mammalian AVP. This receptor reacts to the V₁ agonist but probably not to the V₁ antagonist.     

Interleukin-1 (IL-1) depresses cytochrome P450 levels and activities in mice

Endotoxin depresses cytochrome P450 levels when injected into animals. The purpose of this study was to determine whether endotoxin itself, or monokine(s) released in response to endotoxin administration are responsible for this effect. Cytochrome P450 levels and drug metabolizing activities were measured in endotoxin resistant C3H/HeJ mice 24h after single intraperitoneal injections of either lipopolysaccharide (LPS), a semipurified murine monokine preparation containing interleukin-1 (IL-1), or murine recombinant IL-1. In endotoxin sensitive C3H/HeN mice, LPS (0.5 mg/Kg) decreased total cytochrome P450 levels, benzphetamine demethylase activities, and ethoxyresorufin-0-deethylase activities. This dose of LPS did not alter cytochrome P450 levels or activities in the C3H/HeJ mice. However, after injection of the semipurified monokine preparation or the recombinant IL-1, there were significant decreases in cytochrome P450 levels and activities similar to the decreases observed with LPS in the C3H/HeN mice. These findings suggest that the alterations in hepatic cytochrome P450 seen with endotoxin injection are mediated, at least in part, by IL-1.     

Central and peripheral injections of ACTH (1–24) reduce fever in adrenalectomized rabbits

Central administration of ACTH (1-24) reduces fever in normal rabbits in doses that have no effect on afebrile body temperature. Previous experimental and clinical reports indicate that peripheral administration of both ACTH and corticosteroids reduces fever, and since central injection of corticosteroids can also lower fever it might be that the antipyretic effect of intracerebroventricular (ICV) ACTH (1-24) is due to adrenal stimulation. To learn whether this endogenous central peptide can produce antipyresis independently, ACTH (1-24) was injected ICV in bilaterally adrenalectomized (ADX) rabbits made febrile by IV injections of leukocytic pyrogen (LP). ACTH (250 ng) given ICV reduced fever in these animals and had a slight hypothermic effect when given to the same rabbits when they were afebrile. Doses of 25-75 ng reduced fever without influencing normal body temperature. Intravenous injections of ACTH (2.5 micrograms) also lowered fever caused by IV LP in ADX rabbits. The present findings raise the possibility that release of endogenous central ACTH, and perhaps entry into the brain of circulating ACTH, the release of which is known to increase in fever, limits the magnitude of the febrile response by influencing central temperature controls.     

Febrile tolerance develops in response to repeated administration of bacterial lipopolysaccharide but not of interleukin-1β in rats

Changes of abdominal temperature in response to intraperitoneal injections of 100 μg/kg bacterial lipopolysaccharide (LPS), repeated three times in intervals of 3 days were measured in rats. Only after the first injection of LPS a pronounced fever developed, a small fever was recorded after the second injection, while the response to the 3rd injection of LPS was almost the same as to an administration of solvent (0.9 % saline) to naive rats. Levels of bioactive cytokines (tumor necrosis factor α, TNFα, and interleukin-6, IL-6), measured 60 min after the 1st, 2nd or 3rd injection of LPS, were progressively attenuated. Changes of abdominal temperature in response to intraperitoneal injections of recombinant rat-interleukin-1β (rr IL-1β), also repeated three times in intervals of 3 days were measured in another group of rats. The febrile responses to the 1st, 2nd and 3rd injection of rr IL-1β were amost identical. The results of this study show that febrile tolerance develops in response to repeated injections of LPS, but not of its putative endogenous mediator, IL-1β, in rats.     

Central activation of thermogenesis and fever by interleukin-1 beta and interleukin-1 alpha involves different mechanisms

Interleukin-1 exists in two forms (alpha and beta) which are assumed to act on the same receptor. Both forms of the molecule stimulated fever and thermogenesis in the rat when injected into the brain, but interleukin-1 beta was more effective, and combined injection of alpha and beta elicited additive responses. The actions of interleukin-1 beta were inhibited by pretreatment of the animals with either a receptor antagonist or monoclonal antibody to corticotrophin releasing factor. The effects of interleukin-1 alpha were unaltered by these treatments. The results indicate that brain corticotrophin releasing factor mediates thermogenesis and fever induced by interleukin-1 beta but not by interleukin-1 alpha.     

The immunomodulatory effects of tuftsin on the non-specific immune system of Indian Major carp, Labeo rohita

The purpose of this study was to determine if injections of different dosages of tuftsin would enhance the immune response and disease resistance against the infections due to the opportunistic pathogens Aeromonas hydrophila and Edwardsiella tarda in Labeo rohita fingerlings. Hence, four different dosages of tuftsin in PBS suspension at the rate of 0, 5, 10, 15 mg kg(-1) body weight of fish were injected intraperitoneally to the fingerlings of L. rohita at 2-week intervals for four times. After every 2-week interval, different serum biochemical, haematological and immunological parameters of fish were evaluated. Biochemical and haematological parameters including serum total protein content, albumin content, globulin content, albulin:globulin ratio, glucose content, leucocyte counts etc.; cellular immune parameters including superoxide anion production, phagocytic activities, lymphokine production index etc.; humoral immune parameters including lysozyme activity, complement activity, serum bactericidal activity etc., in the fish were evaluated after every 2-week interval. After 56 days, fish were divided into two subgroups under each major treatment group for challenge with two pathogens A. hydrophila and E. tarda. The mortality (%) and agglutinating antibody titre was recorded on 28th day post challenge. Most of the immune parameters including leucocyte count, phagocytic ratio, phagocytic index, lysozyme activity, complement activity, and serum bactericidal activity were significantly (p相似文献   

5-HT1-, but not 5-HT2-serotonergic, M1-, M2-muscarinic cholinergic or dopaminergic receptors mediate the ACTH/cortisol response to metoclopramide in man

The possible mediation of dopaminergic, muscarinic cholinergic and/or serotonergic receptors in the response of ACTH/cortisol to metoclopramide (MCP) was evaluated in 27 normal men. All subjects were tested with MCP (10 mg in an intravenous bolus plus placebo or saline, NaCl 0.9%, control test). For the other tests (experimental tests), the men were divided into three groups of 9 subjects each. One group was tested with MCP in the presence of the dopaminergic agonist bromocriptine (5 mg p.o. 3 h before MCP), another group was tested with MCP plus the M1- and M2-muscarinic-cholinergic antagonist atropine (1.2 mg in an intravenous bolus, just before MCP) or the M1-muscarinic receptor blocker pirenzepine (40 mg in an intravenous bolus 10 min before MCP). The third group was tested with MCP after treatment with the selective 5-HT1-serotonergic receptor blocker metergoline (10 mg/day p.o. in 5 divided doses for 4 days before MCP) or the 5-HT2-serotonergic receptor antagonist ketanserin (10 mg as a slow 3-min intravenous injection, 5 min before MCP). ACTH and cortisol rose by 45 and 55%, respectively, in response to MCP. The basal levels of ACTH and cortisol were not modified by bromocriptine, atropine, pirenzepine, metergoline or ketanserin treatment. Both ACTH and cortisol responses to MCP did not change significantly after bromocriptine, atropine, pirenzepine or ketanserin administration, whereas they were completely abolished by pretreatment with metergoline. Additional experiments were performed in order to evaluate whether the effect of metergoline on the ACTH/cortisol response to MCP depends on the amount of the serotonergic antagonist (dose-response study).(ABSTRACT TRUNCATED AT 250 WORDS)     

Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats

N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin receptors are required for induction, but not maintenance, of pLTF. However, because NMDA and non-NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O(2)) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (+/-)-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist, 1.5 mg/kg) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA antagonist, 10 mg/kg) was systemically (ip) injected approximately 30 min before hypoxia. APV was also injected immediately after or 20 min after episodic hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1-2 days before. Regardless of being injected before or after episodic hypoxia, vehicle did not alter vLTF ( approximately 23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast, CNQX enhanced vLTF ( approximately 34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of NMDA but not non-NMDA receptors is necessary for formation and maintenance of vLTF in awake rats.     

Prostaglandin E2 and fever: a continuing debate

Prostaglandin (PG) E2 is a potent hyperthermic agent and has been assigned an intermediary function in the response of thermoregulatory neurons to pyrogens. Though attractive, this idea has been challenged on several grounds. The present study confirms that brain PGE2 synthesis increases during fever, the time course of the elevation according with a causative role of the compound. Our experimental data also argue against the involvement of a second cyclooxygenase product, specifically thromboxane (TX) A2, in the action of pyrogens. The sequence of events leading to PGE2 production and fever differs depending on the pyrogen, bacterial vs. leucocytic, and its route of administration. Blood-borne interleukin-1 (IL-1) acts on a discrete site in the central nervous system (CNS) which is tentatively identified with the organum vasculosum laminae terminalis (OVLT). The same site may also be the target for blood-borne endotoxin. In addition, endotoxin may promote PGE2 synthesis in the cerebral microvasculature. Both pyrogens, on the other hand, act diffusely throughout the CNS when given intrathecally. We conclude that PGE2 is well suited for an intermediary role in the genesis of fever and ascribe the reported inconsistencies to methodological factors.