Anteroventral Preoptic Region Research Articles

Functional role for preoptic CB1 receptors in breathing and thermal control

The anteroventral preoptic region (AVPO) of the hypothalamus is involved in both temperature and breathing regulation. This area densely express cannabinoid receptors type 1 (CB1) that modulate both excitatory and inhibitory synaptic transmission. However, it is still unknown if the endocannabinoid system located in the AVPO participates in breathing control and thermoregulation. Therefore, we tested the participation of CB1 in the AVPO in the modulation of ventilation and thermal control during normoxia and hypoxia. To this end, body temperature (Tb) of Wistar rats was monitored by datallogers and ventilation (VE) by whole body plethysmography before and after intra-AVPO microinjection of AM-251 (CB1 antagonist, 50 and 100 pmol) followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of the higher dose of AM-251 increased VE but did not change Tb under resting conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced anapyrexia and hyperventilation after vehicle microinjection. The higher dose of the cannabinoid antagonist increased the hypoxia-induced hyperventilation, in the same magnitude as observed under normoxic condition, whereas the drop in Tb elicited by hypoxia was attenuated. Therefore, the present results demonstrate that the endocannabinoid system acting on CB1 receptors in the AVPO exerts a tonic inhibitory modulation on breathing but seem not be involved in thermoregulation during resting conditions. In addition, activation of CB1 receptors in the AVPO stimulate thermal response during hypoxia, reducing energetically expensive responses, such as the hypoxic hyperventilation.

Neuroinflammation in the NTS is associated with changes in cardiovascular reflexes during systemic inflammation

BackgroundLipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status.MethodsWe combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg−1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate.ResultsLPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1β levels in the NTS.ConclusionsThe present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.

Central fractalkine stimulates central prostaglandin E2 production and induces systemic inflammatory responses

Fractalkine (FKN; CX3CL1) belongs to gamma-chemokine family and binds to CX3CR1 receptors. Currently, the mechanisms involving FKN-induced inflammatory mediators are research targets in an attempt to study immune diseases mechanisms. Besides, FKN seems to modulate inflammation in the nervous system by inducing the secretion of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 is a classic and important mediator of fever that activates warm-responsive neurons in the anteroventral preoptic region of the hypothalamus (AVPO). Here, we tested the hypothesis that central FKN modulates febrigenic signaling both centrally and peripherally. We performed intracerebroventricular (icv) microinjections of saline (1 μL) or FKN (doses of 5, 50, 500 pg/μL) in rats and measured body temperature (Tb) besides assessing tail skin temperature (Tsk) as a thermoeffector indicator used to calculate the heat loss index (HLI). We also measured the time course changes in AVPO PGE2, besides plasma corticosterone (CORT) and interleukin-6 (IL-6) levels. FKN induced a long lasting febrile response in which the highest dose (500 pg/μL) induced a marked rise on Tb that was accompanied by a reduced Tsk and HLI, consequently. FKN increased AVPO PGE2 production in a time-dependent manner besides increasing plasma CORT and IL-6 levels. Our data consistently indicate that FKN increases AVPO PGE2 production and Tb, accompanied by raised plasma IL-6 levels and activation of the hypothalamus-pituitary-adrenal axis.

Central Fractalkine Induces Systemic Inflammation Independently of Hypothalamic Prostaglandin E2

Fractalkine (FKN; CX3CL1) belongs to the gamma‐chemokine family and binds to CX3CR1 receptors. Currently, the mechanisms involving FKN‐induced inflammatory mediators are research targets in an attempt to study immune diseases mechanisms. Besides, FKN seems to modulate inflammation in the nervous system by inducing the secretion of pro‐inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 is a classic and important mediator of fever that activates warm‐responsive neurons in the anteroventral preoptic region of the hypothalamus (AVPO). Here, we tested the hypothesis that central FKN modulates febrigenic signaling both centrally and peripherally. Thus, male Wistar rats (280–350 g, n=5/group) were obtained from the Central Animal Facility at the University of São Paulo in Ribeirão Preto and all the experiments were performed according to the Brazilian society of laboratory animals science and in conformance with the FASEB Statement of Principles for the use of animals in research and education. We performed intracerebroventricular (icv) microinjections of saline (1 μL) and FKN (doses of 5, 50, 500 pg/μL) and measured body temperature (Tb), besides assessing tail skin temperature (Tsk) as a thermoeffector indicator. We also measured AVPO PGE2, plasma corticosterone (CORT) and interleukin‐6 (IL‐6) levels. FKN induced a long lasting febrile response in which the highest dose (500 pg/μL) induced a marked rise on Tb that was accompanied by a reduced Tsk. FKN had no effect on AVPO PGE2 production, whereas caused increases in plasma CORT and IL‐6 levels. Our data consistently indicate that FKN induces fever (reducing Tsk) in a PGE2 independent way probably by increasing plasma IL‐6 levels.Support or Funding InformationThe São Paulo Research Foundation (FAPESP) grant numbers #16/17681‐9 and #17/01633‐8 and the National Council for Scientific and Technological Development (CNPq), Brazil.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Central serotonin attenuates LPS-induced systemic inflammation

Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280–350g, 8–9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25±1°C), light (06:00–18:00) and humidity (60–65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) – the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100μg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40μg/μL) and measured Tb (“hallmark” of SI), AVPO prostaglandin E2 [(PGE2) – an essential mediator of fever] and prostaglandin D2 [(PGD2) – a cryogenic mediator], plasma corticosterone [(CORT) – a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) – an immune mediator] levels. Detection limits of PGE2, PGD2, CORT and IL-6 assays were 39.1–2500pg/mL, 19.5–2500pg/mL, 0.12–2000μg/dL, and 0.125–8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE2 (whereas PGD2 remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40μg/μL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10μg/μL) microinjection prevented the LPS-induced increases in AVPO PGE2 (whereas not altering PGD2), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE2 synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases.

Cryogenic role of central endogenous hydrogen sulfide in the rat model of endotoxic shock

Thermoregulatory responses to lipopolysaccharide (LPS) are affected by modulators that increase (propyretic) or decrease (cryogenic) body temperature (Tb). We tested the hypothesis that central hydrogen sulfide (H2S) acts as a thermoregulatory modulator and that H2S production in the anteroventral preoptic region of the hypothalamus (AVPO) is increased during hypothermia and decreased during fever induced by bacterial lipopolysaccharide (LPS, 2.5mg/kg i.p.) in rats kept at an ambient temperature of 25°C. Deep Tb was recorded before and after pharmacological inhibition of the enzyme cystathionine β-synthase (CBS – responsible for H2S endogenous production in the brain) combined or not with LPS administration. To further investigate the mechanisms responsible for these thermoregulatory adjustments, we also measured prostaglandin D2 (PGD2) production in the AVPO. LPS caused typical hypothermia followed by fever. Levels of AVPO H2S were significantly increased during hypothermia when compared to both euthermic and febrile rats. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100 pmol) neither affected Tb nor basal PGD2 production during euthermia. In LPS-treated rats, AOA caused increased Tb values during hypothermia, along with enhanced PGD2 production. We conclude that the gaseous messenger H2S modulates hypothermia during endotoxic shock, acting as a cryogenic molecule.

Anteroventral pre‐optic neurones, control of breathing and H2S: physiology or toxicology?

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Endogenous preoptic hydrogen sulphide attenuates hypoxia-induced hyperventilation

We hypothesized that hydrogen sulphide (H2 S), acting specifically in the anteroventral preoptic region (AVPO - an important integrating site of thermal and cardiorespiratory responses to hypoxia in which H2 S synthesis has been shown to be increased under hypoxic conditions), modulates the hypoxic ventilatory response. To test this hypothesis, we measured pulmonary ventilation (V˙E) and deep body temperature of rats before and after intracerebroventricular (icv) or intra-AVPO microinjection of aminooxyacetate (AOA; CBS inhibitor) or Na2 S (H2 S donor) followed by 60 min of hypoxia exposure (7% O2 ). Furthermore, we assessed the AVPO levels of H2 S of rats exposed to hypoxia. Control rats were kept under normoxia. Microinjection of vehicle, AOA or Na2 S did not change V˙E under normoxic conditions. Hypoxia caused an increase in ventilation, which was potentiated by microinjection of AOA because of a further augmented tidal volume. Conversely, treatment with Na2 S significantly attenuated this response. The in vivo H2 S data indicated that during hypoxia the lower the deep body temperature the smaller the degree of hyperventilation. Under hypoxia, H2 S production was found to be increased in the AVPO, indicating that its production is responsive to hypoxia. The CBS inhibitor attenuated the hypoxia-induced increase in the H2 S synthesis, suggesting an endogenous synthesis of the gas. These data provide solid evidence that AVPO H2 S production is stimulated by hypoxia, and this gaseous messenger exerts an inhibitory modulation of the hypoxic ventilatory response. It is probable that the H2 S modulation of hypoxia-induced hyperventilation is at least in part in proportion to metabolism.

Hydrogen sulfide inhibits preoptic prostaglandin E2 production during endotoxemia

Hydrogen sulfide (H2S) is a gaseous neuromodulator endogenously produced in the brain by the enzyme cystathionine β-synthase (CBS). We tested the hypothesis that H2S acts within the anteroventral preoptic region of the hypothalamus (AVPO) modulating the production of prostaglandin (PG) E2 (the proximal mediator of fever) and cyclic AMP (cAMP). To this end, we recorded deep body temperature (Tb) of rats before and after pharmacological modulation of the CBS–H2S system combined or not with lipopolysaccharide (LPS) exposure, and measured the levels of H2S, cAMP, and PGE2 in the AVPO during systemic inflammation. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100pmol) did not affect basal PGE2 production and Tb, but enhanced LPS-induced PGE2 production and fever, indicating that endogenous H2S plays an antipyretic role. In agreement, icv microinjection of a H2S donor (Na2S; 260nmol) reduced the LPS-induced PGE2 production and fever. Interestingly, we observed that the AVPO levels of H2S were decreased following the immunoinflammatory challenge. Furthermore, fever was associated with decreased levels of AVPO cAMP and increased levels of AVPO PGE2. The LPS-induced decreased levels of cAMP were reduced to a lesser extent by the H2S donor. The LPS-induced PGE2 production was potentiated by AOA (the CBS inhibitor) and inhibited by the H2S donor. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated during endotoxemia favoring PGE2 synthesis and lowering cAMP levels in the preoptic hypothalamus.

Hydrogen sulfide as a cryogenic mediator of hypoxia-induced anapyrexia

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been aptly called anapyrexia, but the mechanisms involved are not completely understood. The roles played by nitric oxide (NO) and other neurotransmitters have been documented during hypoxia-induced anapyrexia, but no information exists with respect to hydrogen sulfide (H 2S), a gaseous molecule endogenously produced by cystathionine β-synthase (CBS). We tested the hypothesis that H 2S production is enhanced during hypoxia and that the gas acts in the anteroventral preoptic region (AVPO; the most important thermosensitive and thermointegrative region of the CNS) modulating hypoxia-induced anapyrexia. Thus, we assessed CBS and nitric oxide synthase (NOS) activities [by means of H 2S and nitrite/nitrate (NO x) production, respectively] as well as cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) levels in the anteroventral third ventricle region (AV3V; where the AVPO is located) during normoxia and hypoxia. Furthermore, we evaluated the effects of pharmacological modifiers of the H 2S pathway given i.c.v. or intra-AVPO. I.c.v. or intra-AVPO microinjection of CBS inhibitor caused no change in Tb under normoxia but significantly attenuated hypoxia-induced anapyrexia. During hypoxia there were concurrent increases in H 2S production, which could be prevented by CBS inhibitor, indicating the endogenous source of the gas. cAMP concentration, but not cGMP and NO x, correlated with CBS activity. CBS inhibition increased NOS activity, whereas H 2S donor decreased NO x production. In conclusion, hypoxia activates H 2S endogenous production through the CBS-H 2S pathway in the AVPO, having a cryogenic effect. Moreover, the present data are consistent with the notion that the two gaseous molecules, H 2S and NO, play a key role in mediating the drop in Tb caused by hypoxia and that a fine-balanced interplay between NOS-NO and CBS-H 2S pathways takes place in the AVPO of rats exposed to hypoxia.

Role of preoptic opioid receptors in the body temperature reduction during hypoxia

Evidence indicates that endogenous opioids play a role in body temperature (Tb) regulation in mammals but no data exist about the involvement of the specific opioid receptors, mu, kappa and delta, in the reduction of Tb induced by hypoxia. Thus, we investigated the participation of these opioid receptors in the anteroventral preoptic region (AVPO) in hypoxic decrease of Tb. To this end, Tb of unanesthetized Wistar rats was monitored by temperature data loggers before and after intra-AVPO microinjection of the selective kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI; 0.1 and 1.0 μg/100 nL/animal), the selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 cyclic (CTAP; 0.1 and 1.0 μg/100 nL/animal), and the selective delta-opioid receptor antagonist Naltrindole (0.06 and 0.6 μg/100 nL/animal) or saline (vehicle, 100 nL/animal), during normoxia and hypoxia (7% inspired O 2). Under normoxia, no effect of opioid antagonists on Tb was observed. Hypoxia induced Tb to reduce in vehicle group, a response that was inhibited by the microinjection intra-AVPO of nor-BNI. In contrast, CTAP and Naltrindole did not change Tb during hypoxia but caused a longer latency for the return of Tb to the normoxic values just after low O 2 exposure. Our results indicate the kappa-opioid receptor in the AVPO is important for the reduction of Tb during hypoxia while the mu and delta receptors are involved in the increase of Tb during normoxia post-hypoxia.

Serotoninergic receptors in the anteroventral preoptic region modulates the hypoxic ventilatory response

Hypothalamus is a site of integration of the hypoxic and thermal stimuli on breathing and it is known that serotonin (5-HT) receptors in the anteroventral preoptic region (AVPO) of the hypothalamus mediate hypoxic hypothermia. Once 5-HT plays a role in the hypoxic ventilatory response (HVR), we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2 and 5-HT7) into the AVPO in the hypoxia-induced hyperventilation. To this end, pulmonary ventilation (VE) of male Wistar rats was measured before and after intra-AVPO microinjection of vehicles, methysergide (5-HT1/5-HT2 receptor antagonist, 0.2 and 2 μg/100 nL), WAY 100635 (5-HT1A receptor antagonist, 0.3 and 3 μg/100 nL) and SB 269970 (5-HT7 receptor antagonist, 0.4 and 4 μ/100 nL), followed by 1h of 7% O2 exposure. Vehicles or 5-HT antagonists did not change VE during normoxia. Exposure to 7% of inspired O2 evoked typical hypoxia-induced hyperventilation, which was not affected by vehicle and both doses of methysergide. However, WAY 100635 and SB 269970 injections caused an increased HVR, due to a higher tidal volume. The effect was more pronounced with the 5-HT7 antagonist since both doses were capable of increasing the HVR. As to the 5-HT1A antagonist, the increase of HVR was observed at the lower dose only. Therefore, the current data provide the evidence that 5-HT acting on 5-HT1A and 5-HT7 receptors in the AVPO exert an inhibitory effect on the HVR.

Respiratory and body temperature modulation by adenosine A1 receptors in the anteroventral preoptic region during normoxia and hypoxia

The present study was undertaken to investigate adenosine as a simultaneous mediator of hypoxia-induced hyperventilation and regulated hypothermia in the anteroventral preoptic region (AVPO), the thermointegrative region of the central nervous system (CNS). Accordingly, we predicted that injection of aminophylline and DPCPX, non-selective and A(1) receptor antagonists, respectively, into the AVPO would exacerbate the ventilatory response and lessen the drop in body temperature (T(b)) caused by hypoxia. We measured ventilation (V ) and T(b) of conscious Wistar rats before and after AVPO injection of aminophylline (1 and 10 microg/100 nL) or DPCPX (17.5 and 175 ng/100 nL), or their respective vehicles, followed by 30 min of hypoxia (7% O(2)). Vehicles and the lower doses of both antagonists had no effect on V and T(b) during normoxia or hypoxia. The higher doses of aminophylline and DPCPX increased (P<0.05) the hypoxia-induced hyperventilation, whereas the drop in T(b) elicited by hypoxia was attenuated (P<00.05) by DPCPX only. This higher DPCPX dose also increased T(b) during normoxia. The present data is consistent with the notion that adenosine plays an inhibitory role in respiratory and metabolic regulation, in a way that A(1) receptors stimulation in the AVPO inhibits ventilatory drive during hypoxia and tonically modulates basal T(b).

Serotoninergic receptors in the anteroventral preoptic region modulate the hypoxic ventilatory response

Hypothalamus is a site of integration of the hypoxic and thermal stimuli on breathing and there is evidence that serotonin (5-HT) receptors in the anteroventral preoptic region (AVPO) mediate hypoxic hypothermia. Once 5-HT is involved in the hypoxic ventilatory response (HVR), we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2 and 5-HT7) in the AVPO in the HVR. To this end, pulmonary ventilation (V(E)) of rats was measured before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist), WAY-100635 (a 5-HT1A receptor antagonist) and SB-269970 (a 5-HT7 receptor antagonist), followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of vehicles or 5-HT antagonists did not change V(E) during normoxic conditions. Exposure of rats to 7% O2 evoked typical hypoxia-induced hyperpnea after vehicle microinjection, which was not affected by methysergide. WAY-100635 and SB-269970 treatment caused an increased HVR, due to a higher tidal volume. Therefore, the current data provide the evidence that 5-HT acting on 5-HT1A and 5-HT7 receptors in the AVPO exert an inhibitory modulation on the HVR.

Involvement of serotoninergic receptors in the anteroventral preoptic region on hypoxia-induced hypothermia

Hypoxia causes a regulated decrease in body temperature (Tb). There is circumstantial evidence that the neurotransmitter serotonin (5-HT) in the anteroventral preoptic region (AVPO) mediates this response. However, which 5-HT receptor(s) is (are) involved in this response has not been assessed. Thus, we investigated the participation of the 5-HT receptors (5-HT 1, 5-HT 2, and 5-HT 7) in the AVPO in hypoxic hypothermia. To this end, Tb of conscious Wistar rats was monitored by biotelemetry before and after intra-AVPO microinjection of methysergide (a 5-HT 1 and 5-HT 2 receptor antagonist, 0.2 and 2 μg/100 nL), WAY-100635 (a 5-HT 1A receptor antagonist, 0.3 and 3 μg/100 nL), and SB-269970 (a 5-HT 7 receptor antagonist, 0.4 and 4 μ/100 nL), followed by 60 min of hypoxia exposure (7% O 2). During the experiments, the mean chamber temperature was 24.6 ± 0.7 °C (mean ± SE) and the mean room temperature was 23.5 ± 0.8 °C (mean ± SE). Intra-AVPO microinjection of vehicle or 5-HT antagonists did not change Tb during normoxic conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced hypothermia after vehicle microinjection, which was not affected by both doses of methysergide. However, WAY-100635 and SB-269970 treatment attenuated the drop in Tb in response to hypoxia. The effect was more pronounced with the 5-HT 7 antagonist since both doses (0.4 and 4 μg/0.1μL) were capable of attenuating the hypothermic response. As to the 5-HT 1A antagonist, the attenuation of hypoxia-induced hypothermia was only observed at the higher dose. Therefore, the present results are consistent with the notion that 5-HT acts on both 5-HT 1A and 5-HT 7 receptors in the AVPO to induce hypothermia, during hypoxia.

Evidence for thermoregulation by dopamine D1 and D2 receptors in the anteroventral preoptic region during normoxia and hypoxia

Hypoxia causes a regulated decrease in body temperature (Tb), a response that has been called anapyrexia. Stimulation of dopamine receptors in the central nervous system (CNS) reduces Tb in rats, and dopamine D1 and D2 receptors seem to be involved in this response. Thus, we predicted that injection of SCH 23390 and haloperidol, D1 and partly D2 receptor antagonists, respectively, into the anteroventral preoptic region (AVPO, the thermointegrative region of the CNS) would lessen the hypoxia-induced anapyrexia. We measured Tb of conscious Wistar rats before and after injection of SCH 23390 (50 and 100 ng/100 nl) or haloperidol (50 e 500 ng/100 nl) or their respective vehicles (saline and DMSO 5%) into the AVPO followed by 30 min of hypoxia (7% O 2). Vehicles and the lower doses of SCH 23390 and haloperidol had no effect on Tb during normoxia or hypoxia. The higher doses of SCH 23390 and haloperidol attenuated ( P<0.05) the drop in Tb elicited by hypoxia. However, this higher haloperidol dose also increased Tb during normoxia. The present data is consistent with the notion that dopamine is an important thermoregulatory neurotransmitter in a way that D2 receptors are mainly involved with maintenance of Tb in euthermia, while D1 receptors are activated to induce hypoxic anapyrexia in the AVPO.

Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain.

We tested the hypothesis that nitric oxide (NO) acts in the anteroventral preoptic region (AVPO) modulating fever. To this end, body core temperature (T(c)) of rats was monitored by biotelemetry before and after pharmacological modulation of the NO pathway. Nitrite/nitrate and cGMP in the anteroventral third ventricular region (AV3V), where the AVPO is located, were also determined. Intra-AVPO microinjection of the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 12.5 microg) did not affect basal T(c), but it enhanced the early stage of lipopolysaccharide (LPS) fever, indicating that NO plays an antipyretic role in the AVPO. In agreement, intra-AVPO microinjection of the NO donor sodium nitroprusside (5 microg) reduced T(c). The antipyretic effect of NO seems to be mediated by cGMP because 1) NO has been shown to activate soluble guanylate cyclase, 2) intra-AVPO microinjection of 8-bromo-cGMP (8-BrcGMP) reduced T(c), and 3) the changes in AV3V levels of nitrite/nitrate and cGMP were similar in the course of fever. Additionally, we observed that nitrite/nitrate and cGMP levels decreased in the AV3V after, but not before, the onset of LPS fever, showing that the activity of the NO-cGMP pathway is reduced in the AV3V after intraperitoneal LPS, a mechanism that could contribute to the genesis and maintenance of fever. It was also observed that the efficacy of 8-BrcGMP in reducing T(c) in the AVPO is increased after LPS, emphasizing that the NO-cGMP pathway is antipyretic. This response could explain why intra-AVPO L-NMMA enhanced the early stage of LPS fever, even though the activity of the NO pathway before the onset of fever was unchanged. In summary, these data support an antipyretic role of the NO-cGMP pathway in the AVPO.

Microinjection of a cyclooxygenase inhibitor into the anteroventral preoptic region attenuates LPS fever.

Considerable evidence supports the role of prostaglandins in fever production, but the neuroanatomic sites of prostaglandin synthesis that produce fever remain unknown. With the use of a novel microinjection technique, we injected the cyclooxygenase inhibitor ketorolac into the preoptic area (POA) to determine which preoptic regions produce the prostaglandins required for fever. Initial experiments demonstrated that intravenous ketorolac blocked the fever normally produced by lipopolysaccharide (LPS) 5 micrograms/kg i.v. Microinjection of ketorolac into the POA had no effect on body temperature, and injection of artificial cerebrospinal fluid into the POA did not alter LPS fever. Injection of ketorolac into the anteroventral POA markedly decreased the fever produced by LPS, compared with injections into more rostral, caudal, or dorsal locations. These observations indicate that prostaglandin synthesis in the anteroventral preoptic region is necessary for the production of fever.

Neuroendocrine Control of Reproduction in Teleosts

Gonadotropin releasing hormone (GnRH) activity has been demonstrated in crude extracts of the hypothalamus of several teleost species. Teleost GnRH is similar to the GnRH in elasmobranchs, reptiles, and birds. Luteinizing hormone–releasing hormone (LH–RH) or its superactive analogues stimulate gonadotropin (GtH) secretion in teleosts and can induce ovulation. The actions of LH–RH or its analogues can be self-potentiated or self-suppressed by previous exposure to low and high doses, respectively, and the fish may also be able to modulate its response by other means. There is no agreement on the distribution in the brain of LH–RH immunoreactive perikarya and nerve fibers in teleosts, but the main sites for perikarya are the nucleus lateral tuberis (NLT), preoptic region and telencephalon. Lesioning the NLT by electrical current or monosodium L-glutamate demonstrates that it has functional involvement in the stimulation of GtH release, presumably via GnRH. The NLT and pineal are involved in regulation of daily cycles of GtH secretion, which have importance in stimulating gonadal activity. A GtH release-inhibitory factor (GRIF) apparently originates in the anteroventral preoptic region. Abolition of GRIF action on the pituitary by destruction of its origin or its neural pathways to the pituitary cause very high serum levels of GtH in sexually mature females and males, and ovulation of the females; regulation of the ovulatory surge of secretion of GtH probably involves abatement of GRIF and stimulation by GnRH. Sex steroids have a negative feedback effect during gonadal recrudescence; the greatest negative feedback influence is during the spawning period. In sexually immature fish estrogens and androgens aromatizable to estrogens have a positive feedback effect to stimulate accumulation of GtH in the pituitary; this positive feedback effect may be part of the mechanism of onset of sexual maturity or gonadal recrudescence in teleosts. Binding sites in the brain for sex steroids have been investigated by autoradiography, and active locations were found in the NLT, preoptic region, area ventralis of the telencephalon, and parts of the posterior hypothalamus, as well as the pituitary. The functional significance of most of these binding sites is not known.Key words: teleosts, gonadotropin, gonadotropin releasing hormone, gonadotropin release-inhibitory hormone, steroid feedback, nucleus lateral tuberis, nucleus preopticus

THE HEAT-REGULATING MECHANISM OF THE BODY

ArticlesTHE HEAT-REGULATING MECHANISM OF THE BODYHenry G. BarbourHenry G. BarbourPublished Online:01 Apr 1921https://doi.org/10.1152/physrev.1921.1.2.295MoreSectionsPDF (4 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Previous Back to Top FiguresReferencesRelatedInformationCited ByCentral nNOS is involved in restraint stress-induced fever: evidence for a cGMP pathwayPhysiology & Behavior, Vol. 80, No. 1Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brainAlexandre A. Steiner, Jose Antunes-Rodrigues, Samuel M. McCann, and Luiz G. S. Branco1 February 2002 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 282, No. 2Antipyretic effect of arginine vasotocin in toadsK. C. Bicego-Nahas, A. A. Steiner, E. C. Carnio, J. Antunes-Rodrigues, and L. G. S. Branco1 June 2000 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 278, No. 6Effect of intracerebroventricular administration of vasopressin on stress-induced hyperthermia in ratsPhysiology & Behavior, Vol. 60, No. 2Criteria for establishing a physiological role for brain peptides. A case in point: the role of vasopressin in thermoregulation during fever and antipyresisBrain Research Reviews, Vol. 14, No. 2Antipyresis due to centrally administered vasopressin differentially alters thermoregulatory effectors depending on the ambient temperatureRegulatory Peptides, Vol. 19, No. 1-2The antipyretic effects of centrally administered vasopressin at different ambient temperaturesBrain Research, Vol. 415, No. 2Potent stimuli for vasopressin release, hypertonic saline and hemorrhage, cause antipyresis in the ratRegulatory Peptides, Vol. 15, No. 4Vasopressin: A homeostatic effector in the febrile processNeuroscience & Biobehavioral Reviews, Vol. 6, No. 2Influence of a hot and humid environment on the patient with coronary heart diseaseJournal of Chronic Diseases, Vol. 4, No. 4PARA-AMINOSALICYLIC ACID IN TUBERCULOSISThe Lancet, Vol. 255, No. 6598Experiments in heatstroke in IranTransactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 32, No. 3The human organism and hot environmentsTransactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 29, No. 1Studies in Water Metabolism of the Cat. The Influence of Dehydration on Blood Concentration, Thermoregulation, Respiratory Exchange, and Metabolic-Water ProductionPhysiological Zoology, Vol. 4, No. 2 More from this issue > Volume 1Issue 2April 1921Pages 295-326 https://doi.org/10.1152/physrev.1921.1.2.295History Published online 1 April 1921 Published in print 1 April 1921 PDF download Metrics Downloaded 6,317 times