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A L Ungar

Publications and source records attributed to A L Ungar.

18 recordsLinked to original sources
PubMed1999

Relation between complement and the febrile response of guinea pigs to systemic endotoxin.

We reported recently that the complement (C) system may play a role in the febrile response of guinea pigs to intravenous lipopolysaccharide (LPS) administration because C depletion abolished the LPS-induced rise in core temperature (T(c)). The present study was designed to investigate further the relation between C reduction [induced by cobra venom factor (CVF); 20, 50, 100, and 200 U/animal iv] and the fever of adult, conscious guinea pigs produced by LPS injected intravenously (2 microg/kg) or intraperitoneally (8, 16, 32 microg/kg) 18 h after CVF; control animals received pyrogen-free saline. Serum C levels were measured as total hemolytic C activity before and 18 h after CVF injection and expressed as CH(100) units. In other experiments, serum C levels were determined at various intervals after the intravenous and intraperitoneal injections at different doses of LPS alone. LPS produced fevers generally of similar heights but of different onset latencies and durations, depending on the dose and route of administration. CVF caused dose-related reductions in serum C, from approximately 1,136 U to below detection. These reductions proportionately attenuated the fevers induced by intraperitoneal LPS, but not by intravenous LPS. Intravenous and intraperitoneal LPS per se caused reductions in serum C of 25 and 40%, respectively, indicating activation of the C cascade. These decreases were transient, however, occurring early during the febrile rise approximately 30 min after LPS injection. These data thus support the notion that the C system may be critically involved in the febrile response of guinea pigs to systemic, particularly intraperitoneal, LPS.

Animals↗
PubMed1998

Complement reduction impairs the febrile response of guinea pigs to endotoxin.

Although it is generally believed that circulating exogenous pyrogens [e.g., lipopolysaccharides (LPS)] induce fever via the mediation of endogenous pyrogens (EP) such as cytokines, the first of these, tumor necrosis factor-alpha, is usually not detectable in blood until at least 30 min after intravenous administration of LPS, whereas the febrile rise begins within 15 min after its administration. Moreover, although abundant evidence indicates that circulating LPS is cleared primarily by liver macrophages [Kupffer cells (KC)], these do not secrete EP in immediate response. This would imply that other factors, presumably evoked earlier than EP, may mediate the onset of the febrile response to intravenous LPS. It is well known that blood-borne LPS very rapidly activates the intravascular complement (C) system, some components of which in turn stimulate the quick release into blood of various substances that have roles in the acute inflammatory reaction. KC contain receptors for C components and are in close contact with afferent vagal terminals in the liver; the involvement of hepatic vagal afferents in LPS-induced fever has recently been shown. In this study, we tested the hypothesis that the initiation of fever by intravenous LPS involves, sequentially, the C system and KC. To test this postulated mechanism, we measured directly the levels of prostaglandin E2 (PGE2) in the interstitial fluid of the preoptic anterior hypothalamus (POA), the presumptive site of the fever-producing controller, of conscious guinea pigs over their entire febrile course, before and after C depletion by cobra venom factor (CVF) and before and after elimination of KC by gadolinium chloride (GdCl3). CVF and GdCl3 pretreatment each individually attenuated the first of the biphasic core temperature (Tc) rises after intravenous LPS, inverted the second into a Tc fall, and greatly reduced the usual fever-associated increase in POA PGE2. We conclude, therefore, that C activation may indeed be pivotal in the induction of fever by intravenous LPS and that substance(s) generated presumably by KC in almost immediate reaction to the presence of LPS and/or C may transmit pyrogenic signals via hepatic vagal afferents to the POA, where they rapidly induce the production of PGE2 and, hence, fever.

Animals↗
PubMed1996

Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs.

Prostaglandin E2 (PGE2) is postulated to be a central mediator of fever. It is generally believed that it is produced in the preoptic area of the anterior hypothalamus (POA) because, among other evidence, its level increases both in the third ventricle and in the POA in response to pyrogens. However, lately, the question has arisen whether PGE2 might, in fact, be formed outside of the brain substance and then penetrate it, in particular through the organum vasculosum laminae terminalis. If produced outside the brain substance, the peripheral blockade of its synthesis should prevent lipopolysaccharides (LPS)-induced fever, whereas the intracarotid infusion of PGE2 should produce an increase in core temperature (T(C)) as well as in preoptic PGE2. To verify this hypothesis, continuous measurements of T(C) and preoptic PGE2 levels were made in conscious guinea pigs administered the PGE2 synthase inhibitor, indomethacin (10 or 50 mg/kg, im) 30 min before S. enteritidis LPS (2 mu g/kg, iv) or before PGE2 microdialyzed into the POA (1 mu g/mu l at 2 mu g/min for 2.5 h) and during PGE2 infused into a carotid artery (1 mu g and 10 mu g/mu l at 2 mu g/min for 1 h). LPS induced a biphasic 1.4 degrees C fever that was consistently associated with an increase in the level of PGE2 in the POA. Indomethacin at 10 mg/kg attenuated the course of the LPS-induced fever and prevented the associated increase in preoptic PGE2 for 90 min after fever onset; thereafter, PGE2 was significantly reduced by comparison with controls. Indomethacin at 50 mg/kg completely abolished both the fever and the increased levels of PGE2 in the POA; the fever induced by PGE2 microdialyzed into the POA was not affected by indomethacin pretreatment The intracarotid infusion of PGE2 produced T(C) falls and no increase in preoptic PGE2 levels. The indomethacin-induced blockade of fever and inhibition of the associated increase in preoptic PGE2 levels further substantiates the presumptive link between PGE2 in the POA and fever caused by LPS. The failure of exogenous PGE2 infusion to induce increases in T(C) and preoptic PGE2 levels excludes the possibility that PGE2 formed outside of the brain penetrates the POA and induces fever. Thus, in guinea pigs, the PGE2 associated with LPS-induced fever may be synthesized in the POA.

Animals↗
PubMed1996

Interaction between norepinephrine and prostaglandin E2 in the preoptic area of guinea pigs.

The release of norepinephrine (NE) and prostaglandin E2 (PGE2) in the preoptic-anterior hypothalamus (POA) by systemically administered pyrogens suggests that both substances may mediate the febrile response. To investigate their possible interaction, we measured directly the levels of PGE2 in the extracellular fluid of the POA of conscious guinea pigs microdialyzed intrapreoptically with exogenous NE over the entire course of their febrile response to endotoxin. Acidified and buffered NE (NEa, NEb), artificial cerebrospinal fluid (aCSFa, aCSFb), and vehicle (Veha, Vehb) were tested. All but aCSFb depressed the febrile response to endotoxin. The microdialysis of aCSFa, aCSFb, Veha, Vehb, and NEa did not change basal preoptic PGE2 levels. However, NEb, at a dose that by itself did not affect body temperature (Tb), caused a large elevation in preoptic PGE2. The intravenous injection of endotoxin increased the level of PGE2 in the POA. NEb potentiated this increase, whereas NEa, aCSFa, and Vehb reduced it; Veha reduced it for the first 60 min and enhanced it for the last 90 min of the experiment. Thus these data suggest that the low pH of the NE solute and/or its Veh may confound the observed effects of NE on the Tb and preoptic PGE2 induced by endotoxin. We surmise that this is due to a neurotoxic action of the antioxidants and the acidity of the solution on thermosensitive neurons in the POA. Hence, the results of experiments using exogenous, usually acidified, NE preparations that often also contain additives should be interpreted with caution.

Animals↗
PubMed1994

Peripheral naloxone attenuates lipopolysaccharide fever in guinea pigs by an action outside the blood-brain barrier.

We have previously shown that the febrile response of guinea pigs to lipopolysaccharide (LPS) is attenuated by the subcutaneous administration of the tertiary mu-receptor opioid antagonist naloxone-hydrochloride (Nal-HCl). Because Nal-HCl readily crosses the blood-brain barrier (BBB), this study was undertaken to investigate whether its effect on fever is mediated peripherally or centrally. For this, the effects of 1) Nal-HCl (23 and 46 mumol/kg sc), 2) the quaternary opioid antagonists Nal-methiodide (Nal-mI, 46 and 92 mumol/kg sc) and Nal-methobromide (Nal-mBr, 92 mumol/kg sc), which do not cross the BBB, and 3) intracerebroventricular Nal-HCl (0.25 and 1.25 mumol) on the febrile response to intravenous S. enteritidis LPS (2 micrograms/kg) were investigated in conscious guinea pigs. Under afebrile conditions, both Nal-HCl (whether administered sc or icv) and its quaternary analogues induced hypothermic responses. Peripheral Nal-HCl, Nal-mI, and Nal-mBr also attenuated both phases of the characteristically biphasic LPS fever. The thermal effects of the peripheral opioid antagonists, both tertiary and quaternary, were associated with cutaneous vasodilation. Intracerebroventricularly administered Nal-HCl did not evoke any attenuation of fever. The analysis of the data shows that Nal-HCl possesses three different thermoregulatory actions: a central hypothermic action, a peripheral thermolytic action (which is due to, at least partly, cutaneous vasodilation), and a peripheral antipyretic action. The latter effect suggests that, in guinea pigs, circulating opioids may have a role in fever production.

Animals↗
PubMed1993

Genesis of biphasic thermal response to intrapreoptically microinjected clonidine.

Intrapreoptic (IPO) microinjections of various agents cause unavoidable brain tissue injury, often resulting in prostaglandin (PG)-mediated core temperature (Tc) rises. However, IPO microinjection of the alpha 2-adrenoreceptor agonist clonidine (Clo) generally evokes a Tc fall, seemingly avoiding the influence of injury due to the microinjection procedure per se. To clarify this, we microinjected bilaterally into the preoptic/anterior hypothalamus of conscious guinea pigs various doses of Clo dissolved in pyrogen-free saline (PFS, 1 microliter/side). Clo caused biphasic hypo-/hyperthermic responses. The initial hypothermia was dose dependent: no decrease in Tc for 0.1 microgram of Clo, -0.4 +/- 0.1 degree C for 0.5 microgram, -0.9 +/- 0.1 degree C for 1.5 microgram, and -1.2 +/- 0.1 degree C for 5.0 micrograms. During the hyperthermic phase, Tc increased to a dose-independent level (1.0-1.5 degrees C), remaining there up to 5 h postinjection. PFS microinjected IPO also induced hyperthermia, but without any initial Tc decrease. This Tc rise was delayed by 100 min when the cyclooxygenase inhibitor indomethacin (Indo, 50 micrograms/microliters) was injected. Nontreated animals (time controls) maintained Tc at baseline levels during the whole experiment. The alpha 2-antagonist rauwolscine (2 micrograms/side), microinjected IPO 10 min before Clo (0.5 microgram/side), abolished the hypothermic without affecting the hyperthermic response phase; Indo (10 mg/kg), injected intramuscularly 20 min after the IPO microinjection of Clo (0.5 microgram), significantly attenuated the hyperthermic phase. These results confirm that an artifactitious, PG-mediated Tc rise consequent to nonspecific brain tissue injury contaminates the thermal response to agents (hyper- or hypothermizing) microinjected IPO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of intrapreoptic norepinephrine in endotoxin-induced fever in guinea pigs.

The peripheral administration of pyrogens has been shown previously to affect the activity of central noradrenergic neurons, but the effects have been variable and no consensus has emerged regarding their functional significance. Because norepinephrine (NE) microdialyzed into the preoptic area (PO) of the anterior hypothalamus of conscious guinea pigs is hypothermizing, the possibility was investigated whether NE might be a febrilytic rather than a febrigenic mediator. Intravenous injections of Salmonella enteritidis lipopolysaccharide (2.0 micrograms/kg) evoked a bimodal fever, which was attenuated in a dose-dependent manner by NE microdialyzed (10 or 20 micrograms/microliters at a rate of 2 microliters/min for various durations) into the PO. The alpha 2-adrenergic receptor antagonists rauwolscine (1 or 2 micrograms/microliters) and yohimbine (1 microgram/microliter) microdialyzed intrapreoptically significantly reduced the trough of body (core) temperature (Tc) between the first and second peaks of the bimodal fever and prolonged the overall febrile course. None of these effects was associated with changes in skin temperature. The level of NE (assayed by high-performance liquid chromatography with electrochemical detection) in the preoptic extracellular fluid collected by intracerebral microdialysis was significantly elevated at the end of each rising phase of the bimodal fever, just before or about the time when Tc began to fall, compared with pyrogen-free saline controls at the same times. These results suggest that intrapreoptic NE may have a thermolytic effect on fever by reducing metabolic heat production and may thus play a physiological role in the initiation of febrilysis in guinea pigs.

Animals↗
PubMed1992

Validation of the hypothermic action of preoptic norepinephrine in guinea pigs.

Conscious guinea pigs were either microinjected intrapreoptically (iPO) with various doses of norepinephrine (NE) bilaterally or microdialyzed with pyrogen-free saline (PFS) or 10 micrograms/microliters NE unilaterally immediately and unilaterally or bilaterally 2 days after probe insertion. Core temperature (Tco), skin temperature (Tsk), and rate of oxygen consumption (VO2) were monitored continuously. The microinjection of low doses of NE induced Tco rises, whereas that of the highest dose (10 micrograms/microliters) caused an initial Tco fall followed by a rise. The microdialysis of PFS or NE immediately after probe insertion caused Tco rises; the former was abolished and the latter was converted into a fall by indomethacin (Indo, a prostaglandin synthase inhibitor) pretreatment. Two days later, PFS evoked no thermal response whereas NE induced a Tco fall; neither response was affected by Indo pretreatment. The falls in Tco produced by NE microdialyzed uni- or bilaterally were similar. The microdialysis of NE induced a 15% reduction in metabolic rate but no change in Tsk. These results indicate that the Tco rise induced by NE microinjected iPO is a methodological artifact mediated by PGE2, whereas the Tco fall observed in its microdialysis appears to represent the authentic physiological action of this transmitter effected by a reduction in metabolic rate.

Animals↗
PubMed1992

Preoptic norepinephrine-induced hypothermia is mediated by alpha 2-adrenoceptors.

We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area of conscious guinea pigs evokes a fall in core temperature (Tco) that is mediated by a reduction in metabolic rate. To identify the adrenoceptor subtype(s) involved in this effect, we microdialyzed intrapreoptically various adrenergic agonists or antagonists singly or in combinations. Tco and ear skin temperatures of the animals were monitored throughout the experiments. alpha 1-, beta-, beta 1-, and beta 2-agonists and antagonists did not induce significant Tco changes. Although the alpha 2-antagonists yohimbine (Yoh) and rauwolscine (Rau) did not have thermal effects per se, the alpha 2-agonist clonidine evoked dose-dependent Tco falls that were abolished by codialyzed Yoh and Rau. The microdialysis of NE evoked, as before, a 0.7 +/- 0.2 degrees C Tco fall; it was abolished by the codialyzed alpha-antagonist phentolamine, Yoh, and Rau but not by the beta-antagonist propranolol. No adrenoceptor agonist induced changes in ear skin temperature. These results indicate that the hypothermizing effect of intrapreoptically microdialyzed NE is achieved by a reduction in metabolic heat production, mediated by alpha 2-adrenoceptors.

Animals↗
PubMed1990

Neuromodulation of acute-phase responses to interleukin-6 in guinea pigs.

It is now generally recognized that interleukin-6 (IL6) is one of the cytokines that mediate the various nonspecific host defense responses to infectious pathogens. Among its now well-demonstrated effects on systemic administration are fever and acute-phase proteinemia. These effects are also activated by the cytokine, IL1, and it has been shown that they are modulated in the preoptic-anterior hypothalamus (POA). This study was undertaken to determine whether this brain region similarly drives the febrile and proteinemic responses to IL6. We compared, therefore, these responses of conscious guinea pigs to human recombinant (hr)IL6 administered intravenously (IV) and into the POA. hrIL6 given IV was not pyrogenic at 1 microgram/kg, caused low-grade, dose-independent fevers (0.4 +/- 0.1 degree C) at 5-20 micrograms/kg, and dose-related fevers at 50 and 100 micrograms/kg (0.6 +/- 0.0 and 0.9 +/- 0.1 degree C, respectively). However, all doses of hrIL6 induced elevations in the plasma levels of ceruloplasmin (as an indicator of acute-phase proteins), albeit not in a dose-dependent manner. Indomethacin (10 mg/kg, injected intramuscularly 20 min before hrIL6) abolished the febrile response, but did not prevent the rise in plasma ceruloplasmin levels. Fever and ceruloplasminemia were also evoked by 50 and 100 ng of hrIL6 injected into the POA (1 microliter bilaterally), but not by 25 ng. These results indicate that the inductions of fever and plasma ceruloplasmin by IL6 are, like those of IL1, modulated in the POA, albeit the effective doses are much higher than those of IL1.

Acute-Phase Reaction↗
PubMed1984

Glucose protects DBA/2J mice from audiogenic seizures: correlation with brain glycogen levels.

The time courses of changes in liver, blood, and brain cortical glucose and glycogen levels were measured in 21-day-old DBA/2J mice after an IP injection of 10 g/kg glucose. Other mice were injected with glucose and tested for susceptibility to audiogenic seizures (AGS). Susceptibility to AGS fell from maximal levels to complete protection by 4 h, remained low through 6 h, then began to return to control levels by 8 h. Liver, blood, and brain glucose levels all rose to a peak soon after the injection, then fell linearly and returned to control levels by 6-8 h. Changes in brain glycogen levels reflected changes in AGS susceptibility.

Acoustic Stimulation↗
PubMed1984

Temporal changes in liver, blood, and brain glucose, glycogen, and beta-hydroxybutyrate after ethanol in C57BL/6J mice.

The time courses of changes in levels of beta-hydroxybutyrate (BOHB), glucose (GLC), and glycogen (GLY) were measured hourly for 7 h after i.p. 2 g/kg ethanol (ETOH) in samples of liver, blood, and brain in 21 day old C57BL/6J mice. After acute ETOH, brain GLC remained at 2.1 mmol/kg for 2 h, fell to a low of 1.5 mmol/kg at 5 h, then rose slightly. Blood GLC remained near 8 mmol/kg until 3 h, then fell. Liver GLC fell steadily from 10.2 to 7.2 mmol/kg at 7 h. Brain GLY rose from 1.7 to 2.9 mmol/kg at 3 h, then fell steadily. Blood GLY increased from 2.7 to 4.6 mmol/kg at 2 h, then fell to 1.7 mmol/kg. Liver GLY decreased from 70 to 30 mmol/kg. BOHB changes were similar in all samples. BOHB in brain fell from 0.12 to 0.08 mmol/kg at 2 to 3 h; then rose steadily to 0.27 mmol/kg at 7 h. Blood and liver BOHB fell from 0.40 to 0.25 mmol/kg, then rose to 1.0 mmol/kg. In a previous study, susceptibility to audiogenic seizures after 2 g/kg ETOH was completely suppressed for up to 1 h, then susceptibility increased to a maximum at 5 1/2 h, when a period of potentiation was observed. In this study, brain GLY levels were increased during the period of protection, and brain GLC levels were decreased during the period of potentiation. Together, these data may lend support to an hypothesis of an indirect effect of ETOH on the brain, leading to changes in susceptibility to audiogenic seizures via changes in metabolite availability.

3-Hydroxybutyric Acid↗
PubMed1981

Decreased normorphine sensitivity of maternal guinea pig ilea at parturition.

Several approaches have been used by others to explore the possible involvement of endorphins in pregnancy and parturition. We employed the opioid sensitive preparation, the guinea pig ileum, to measure opioid sensitivity in three groups of adult guinea pigs: non-pregnant, near parturition, and a few weeks after parturition. Elevated normorphine EC50s occurred near the time of parturition. At 14-16 days post-partum, the EC50s for normorphine had returned to non-pregnant control levels. These data point to the activation of endorphin systems at the time of parturition.

Animals↗
PubMedDate not supplied

Relief of postlaminectomy syndrome in selected patients by injection of autogenous cerebrospinal fluid.

We have been using the differential spinal block to study patients referred to our Pain Clinic for treatment of their chronic pain syndromes. In a selected group of chronic-pain patients from whom cerebrospinal fluid (CSF) could not be obtained at the L4 or L5 interspace, administration of autogenous CSF obtained at a higher interspace gave immediate and complete but temporary pain relief. Endorphins were present in these autogenous CSF samples. These studies, indicating that CSF even from chronic-pain patients contains analgesic substances (possibly endorphins), may point to new treatment modalities for certain chronic back pain syndromes.

Adult↗