It is generally believed that fever is mediated by certain cytokines produced by immune cells activated by exogenous pyrogens, e.g., lipopolysaccharides (LPS), released into the circulation and transported to the brain There, the cytokines are thought to stimulate prostaglandin (PG) E2 production within the organum vasculosum laminae terminalis region. PGE2 then may act as a febrigenic mediator locally or in the surrounding preoptic area (POA). However, whereas the increases in preoptic PGE2 and body (core) temperature (Tc) following the intravenous (i.v.) administration of LPS correlate temporally, cytokine levels in blood lag both these increases. From recent data in the literature, we have conjectured that a possible, alternative communication pathway between the i.v. LPS-activated immune system and brain PGE2 may be provided by the vagi. To test this possibility, we measured the levels of PGE2 in the extracellular fluid of the POA (collected by microdialysis) of conscious, subdiaphragmatically vagotomized or sham-operated guinea pigs following LPS administration (2 micrograms/kg; i.v.); controls received pyrogen-free saline (PFS). The effluents from the microdialysis probes were collected over 30-min periods throughout the experiments and the samples analyzed by radioimmunoassay; Tc was monitored continuously using thermocouples inserted 5 cm into the colon. LPS induced a biphasic fall in Tc and failed to increase preoptic PGE2 levels in the vagotomized guinea pigs (n = 10), whereas in their sham-operated controls (n = 10) it induced increases in both preopitc PGE2 and Tc within 15 min after its injection; PFS (n = 13) had no effect on either variable. We postulate that peripheral immune cell-derived signals may be transmitted via the vagi to the medulla. From other data, we suggest further that they may be conveyed from here via the ventral noradrenergic bundle to the POA region, where the released norepinephrine induces the local synthesis of PGE2 and, hence, fever onset.

Afferent Pathways↗

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↗

PubMed1996

Heat stroke: opioid-mediated mechanisms.

In our previous study in guinea pigs, intensive and prolonged intraperitoneal heating (IPH) caused heat stroke characterized by high mortality and accompanied by two paradoxical phenomena: ear skin vasoconstriction at a high body temperature (Tb) (hyperthermia-induced vasoconstriction) and a post-IPH Tb fall at an ambient temperature (Ta) below thermoneutrality (hyperthermia-induced hypothermia). In this study, we tested the hypothesis that the mechanisms of the two phenomena involve endogenous opioid agonists. Experiments were conducted in 24 unanesthetized, lightly restrained guinea pigs, each chronically implanted with an intraperitoneal thermode and intrahypothalamic thermocouple. The thermoregulatory effects of a wide-spectrum opioid-receptor antagonist, naltrexone (NTX; 50 or 0 mumol/kg sc), were studied in IPH-induced heat stroke and under normal conditions. IPH was accomplished by perfusing (50 ml/min; 80 min) water (45 degrees C) through the thermode. Ta was maintained at approximately 24 degrees C. Skin vasodilation occurred at the onset of IPH but later changed to vasoconstriction despite high Tb and continuing IPH. IPH-induced hyperthermia (1.8 +/- 0.1 degrees C) was followed by a post-IPH Tb fall (-5.1 +/- 0.7 degree C; calculated for the survivors only). The 48-h mortality rate was 50%. NTX prevented the hyperthermia-induced vasoconstriction and attenuated the hyperthermia-induced hypothermia (-1.8 +/- 0.4 degree C). None of the NTX-treated animals died. The effects of NTX on Tb regulation under normal conditions were minor. These results indicate that the phenomena of both hyperthermia-induced vasoconstriction and hyperthermia-induced hypothermia are opioid dependent. The latter is speculated to reflect opioid-mediated inhibition of metabolism; the former is thought to result from opioid-induced hemodynamic alterations. Because both phenomena did not occur in the NTX-treated survivors, the skin vasoconstriction at high Tb and the posthyperthermia Tb fall may be viewed as markers of the severity of heat stroke. It is suggested that opioid antagonists may have therapeutic potential in heat-induced disorders.

Animals↗

PubMed1995

Biphasic fever: what triggers the second temperature rise?

The mechanism of initiation of the second body temperature (Tb) rise of the typically biphasic lipopolysaccharide (LPS) fever is not known. This study was undertaken to test the hypothesis that the second Tb rise during fever may be initiated as a direct consequence of the elevated Tb of the first febrile rise. Experiments were conducted in conscious guinea pigs implanted with intraperitoneal thermodes, intravenous catheters, and intrahypothalamic thermocouples. Intraperitoneal cooling (IPC) was performed by perfusing water (22 degrees C) through the thermode under afebrile conditions during the first (0-40 min after pyrogen injection) or second (80-120 min) phase of the biphasic LPS (2 g/kg iv) fever or during a monophasic LPS (0.5 g/kg iv) fever. Throughout IPC, the rate of heat withdrawal was maintained at 11.6 +/- 1.2 mW/g. No IPC was performed in the corresponding controls. When started immediately after LPS administration at the higher dose, IPC completely blocked the first phase of the biphasic fever. This blockade was followed by a Tb rise, which, although similar to the rise in the second phase, might alternatively be interpreted as the delayed occurrence of the first phase previously suppressed by IPC. However, we excluded the later possibility by showing the absence of an overshoot in Tb restoration after IPC applied during the second phase of biphasic fever, during monophasic fever, or under afebrile conditions. We conclude, therefore, that the second Tb rise of biphasic LPS fever is not induced by the elevated Tb of the first febrile phase. The cause of the second peak of the characteristic biphasic febrile response to intravenous LPS remains speculative.

Animals↗

PubMed1994

Neuromodulation of fever. A possible role for substance P.

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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

Blockade by interleukin-1 receptor antagonist of IL-1 beta-induced neuronal activity in guinea pig preoptic area slices.

Interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) are thought to be endogenous pyrogens, i.e., to mediate fever production; warm-sensitive (W) and cold-sensitive (C) neurons in the preoptic area (POA) are presumed to be the ultimate targets of endogenous pyrogens. The recent purification of an IL-1 receptor antagonist (IL-1ra) has provided a means for verifying the presumptive action of IL-1 on these neurons. This study was undertaken, therefore, to investigate whether IL-1ra may block the IL-1 alpha and IL-1 beta effects on the firing rates (FR) of W and C neurons in guinea pig POA slices. Human recombinant (hr) IL-1 beta (500 ng/ml) reduced the FR of 26 W neurons and increased those of 3 C neurons recorded; it had no effect on 8 thermally insensitive neurons. hrIL-1 alpha (200-600 ng/ml) did not change the FR of any neuron. IL-Ira (0.01-0.5 mg/ml) had no effect by itself on the FR of all the neurons, but it blocked the hrIL-1 beta-induced FR changes of 24 of the 26 W and of all 3 C neurons when given before the cytokine. The lowest effective dose was 0.05 mg/ml. These results support the hypothesis, therefore, that POA thermosensitive neurons may be direct targets of IL-1 beta and that it may be an endogenous pyrogen acting on these units to induce fever production.

Animals↗

PubMed1992

Hypothalamic neuronal responses to interleukin-6 in tissue slices: effects of indomethacin and naloxone.

We recently reported that human recombinant interleukin-6 (hrIL-6) microinjected into the preoptic area (POA) of guinea pigs induced fever at high doses, suggesting that IL-6 may be another endogenous pyrogen. This study was undertaken to determine whether hrIL-6 affects the single-unit activity of thermosensitive and thermally insensitive neurons in hypothalamic tissue slices and whether indomethacin (Indo) or naloxone (Nal), a cyclooxygenase inhibitor and a mu-opioid receptor antagonist, respectively, influences the effects of hrIL-6 on those neurons. hrIL-6 (2 x 10(3)-8 x 10(3) U/ml) depressed the activity in 50 (83%) of 60 warm-sensitive (W) neurons and excited all 4 cold-sensitive (C) neurons found. It had no effect, however, on 14 (48%) of 29 thermally insensitive (I) neurons, albeit 7 and 8 I neurons decreased and increased their firing rates, respectively. Indo (0.05-1 mg/ml) blocked the effect of hrIL-6 on 22 of 24 W neurons and 2 C neurons tested. Nal(0.1-1 mg/ml) blocked or reduced the effect of hrIL-6 on 21 of 25 W neurons and 1 C neuron recorded. These drugs induced no neuronal response per se. Nal at 2-5 mg/ml, which increased the activity of four W neurons by itself, reversed their depressed response to hrIL-6. These results support the possibility that IL-6-induced fevers may be mediated through an effect on thermosensitive neurons in the POA and that opioids and prostaglandin E may both be involved in this process.

Animals↗