Preoptic Area And Anterior Hypothalamus Research Articles

Effect of oral administration of GABA on thermoregulation in athletes during exercise in cold environments: A preliminary study.

Backgroundγ-aminobutyric acid (GABA), a common ingredient in sports supplements and other health products, regulates body temperature in the preoptic area and anterior hypothalamus (PO/AH). To date, no study has examined the effect of GABA on thermoregulation during exercise in humans in a cold temperature environment (11 ± 0.3°C, 45% ± 2% relative humidity).MethodsWe performed a randomized, double-blind study. Ten trained male athletes consumed either a drink (3 ml/kg weight) containing GABA (1,000 mg, trial G) or an equivalent amount of placebo drink (trial C) before exercise. They rested for 20 min and then cycled at 60% of maximum output power for 40 min, pedaling at 60 rpm, and recovered for 20 min. Core temperature (Tc), skin temperature (upper arm, chest, thigh, calf), and heart rate (HR) were monitored at rest (T0), exercise begins (T20), 20 min of exercise (T40), the exercise ends (T60), and at recovery (T80).ResultsCompared to T0, Tc decreased significantly at T20 and increased significantly at T40, T60 and T80 (p < 0.01). From 35–80 min, the Tc was higher in trial G (peaked at 37.96 ± 0.25°C) than in trial C (37.89 ± 0.37°C), but it failed to reach significant difference (p > 0.05); Tsk continued to increase during exercise and was significantly higher than T0 at T40 (p < 0.05), T60 and T80 (p < 0.01). There was no significant difference in Tsk between the two trials (p > 0.05).ConclusionOur findings provide initial evidence that oral administration of GABA does not affect thermoregulation and has no adverse effects on the body as an ergogenic exercise supplement during exercise in cold environments.

Moderate intensity, exercise-induced catecholamine release in the preoptic area and anterior hypothalamus in rats is enhanced in a warm environment

Thermoeffector responses and core body temperature (Tcore) homeostasis during exercise are affected by both ambient temperature and exercise intensity. We have previously reported that Tcore, heat loss responses, and catecholamine release in the preoptic area and anterior hypothalamus (PO/AH) increased during incremental treadmill running. However, no previous study has examined whether changes in the thermoregulatory responses at warm ambient temperature are related to catecholamine responses during moderate intensity exercise in rats. Therefore, the aim of the present study was to investigate the responsiveness of neurotransmission in the PO/AH to moderate intensity exercise at different ambient temperatures, and to relate this to changes in thermoregulation. We measured the monoamine levels in the PO/AH and the thermoregulatory responses in exercising rats simultaneously using a combination of methods, including in vivo microdialysis, biotelemetry, and animal O2/CO2 metabolism measuring system. On the day of experiments, rats ran for 60min at a speed of 18mmin−1 on a treadmill at a 5% gradient, in an ambient temperature of 23°C or 30°C. Tcore, tail skin temperature (Ttail; an index of heat loss), and oxygen consumption (V̇O2: an index of heat production) were monitored. Dopamine (DA), noradrenaline (NA), and serotonin (5-HT) levels were measured by high performance liquid chromatography (HPLC) with electrochemical detection. Exercise significantly increased the Tcore, Ttail, and V̇O2 values, as well as DA and NA release in the PO/AH at both temperatures, and the increases were more pronounced at the warm ambient temperature. The results suggest that the increase in the Tcore, heat production, and heat loss responses even during moderate intensity running in a warm environment are likely associated with an increase in DA and NA release in the PO/AH region.

Dysfunction of thermoregulation contributes to the generation of hyperthermia-induced seizures

Febrile seizures (FS) are generally defined as seizures taking place during fever. Long-term prognosis, including development of epilepsy and malformation of cognitive function, has been demonstrated after infantile FS. However, the mechanism that triggers seizures in hyperthermic environment is still unclear. We here found that the body temperature of rat pups that experienced experimental FS was markedly decreased (∼28°C) after they were removed from the hyperthermic environment. Both the seizure generation and the temperature drop after seizure attack were abolished by either pre-treatment with chlorpromazine (CPZ), which impairs the thermoregulation, or by an electrolytic lesion of the preoptic area and anterior hypothalamus (PO/AH). However, the non-steroidal anti-inflammatory drug celecoxib did not affect the seizure incidence and the decrease in body temperature after seizure attack. In addition, pentobarbital prevented the generation of seizures, but did not reverse the decrease of body temperature after FS. Therefore, our work indicates that an over-regulation of body temperature occurs during hyperthermic environment, and that the dysfunction of thermoregulation in the PO/AH following hyperthermia contributes to the generation of FS.

Acute intraperitoneal injection of caffeine improves endurance exercise performance in association with increasing brain dopamine release during exercise

The purpose of this study was to examine changes of thermoregulation, neurotransmitters in the preoptic area and anterior hypothalamus (PO/AH), which is the thermoregulatory center, and endurance exercise performance after the intraperitoneal injection of caffeine in rats. Core body temperature (Tcore), oxygen consumption (VO2) and tail skin temperature (Ttail) were measured. A microdialysis probe was inserted in the PO/AH, and samples for the measurements of extracellular dopamine (DA), noradrenaline (NA) and serotonin (5-HT) levels were collected. During the rest experiment, 1h after baseline collections in the chamber (23°C), the rats were intraperitoneally injected with saline, or 3mgkg−1 or 10mgkg−1 caffeine. The duration of the test was 4h. During the exercise experiment, baseline collections on the treadmill were obtained for 1h. One hour before the start of exercise, rats were intraperitoneally injected with either 10mgkg−1 caffeine (CAF) or saline (SAL). Animals ran until fatigue at a speed of 18mmin−1, at a 5% grade, on the treadmill in a normal environment (23°C). At rest, 3mgkg−1 caffeine did not influence Tcore, Ttail, VO2, extracellular DA, NA and 5-HT. 10mgkg−1 caffeine caused significant increases in Tcore, VO2, Ttail and extracellular DA in the PO/AH. In addition, 10mgkg−1 caffeine increased the run time to fatigue (SAL: 104.4±30.9min, CAF: 134.0±31.1min, p<0.05). The combination of caffeine and exercise increased Tcore, VO2, Ttail and extracellular DA in the PO/AH. NA increased during exercise, while neither caffeine nor exercise changed 5-HT. These results indicate that caffeine has ergogenic and hyperthermic effects, and these effects may be related to changes of DA release in the brain.

Continuous monitoring of hypothalamic neurotransmitters and thermoregulatory responses in exercising rats

The purpose of the present study was to investigate the relationship between thermoregulation and catecholamine release in the preoptic area and anterior hypothalamus (PO/AH) during incremental treadmill running in the rat. To this aim, we combined in vivo brain microdialysis, biotelemetry and metabolic measurements for continuous monitoring of core body temperature ( T core), neurotransmitters and thermoregulatory responses. The animals were exercised for 1 h at 23 °C. Treadmill speed was increased every 20 min (10, 20 and 26 m min −1). T core, oxygen consumption ( V ˙ O 2 , an index of heat production) and tail skin temperature ( T tail, an index of heat loss) were simultaneously measured. Brain microdialysis samples were collected every 10 min, and these samples were analyzed for noradrenaline (NA), dopamine (DA) and serotonin (5-HT). T core and V ˙ O 2 significantly increased during treadmill and were exercise intensity dependent. After an initial drop T tail increased significantly during exercise. Both NA and DA levels in the PO/AH increased significantly during exercise. There was no effect on serotonin release. T core, V ˙ O 2 and T tail were positively correlated with the levels of NA and DA. Our data suggest that thermoregulatory responses are dependent on the intensity of the exercise and that these responses are associated with changes in NA and DA release, but not in 5-HT release in the PO/AH.

Serotonin release in the preoptic area and anterior hypothalamus is not involved in thermoregulation during low-intensity exercise in a warm environment

The aim of the present study was to assess the response of serotonin (5-hydroxytryptamine; 5-HT) in the preoptic area and anterior hypothalamus (PO/AH) to thermoregulation during exercise in a warm environment. In addition, it was investigated whether a rapid increase in extracellular 5-HT levels in the PO/AH modifies the thermoregulatory response under the same exercise conditions. Rats were made to run for 120 min at 10 m min −1 on a treadmill at the ambient temperature of 30 °C. Body core temperature ( T core) was monitored using a biotelemetry system, and tail skin temperature ( T tail) was simultaneously measured as an index of heat loss response. Microdialysis in combination with HPLC was used to measure concentrations of monoamines in the PO/AH. Both T core and T tail increased during the first 20 min of exercise and remained stable until the end of the exercise period. Low-intensity exercise did not induce any changes in 5-HT release in the PO/AH, although the levels of norepinephrine and dopamine were increased. Moreover, increased extracellular 5-HT by local perfusion of 1 μM citalopram (selective 5-HT reuptake inhibitor; SSRI) in the PO/AH had no effect on the thermoregulatory response during acute low-intensity exercise in a warm environment. These results suggest that enhanced release of only 5-HT in the PO/AH may not intervene thermoregulation during exercise in a warm environment.

Influence of brain catecholamines on the development of fatigue in exercising rats in the heat.

The purpose of the present study was to identify the effects of an acute injection of a dual dopamine (DA)/noradrenaline (NA) reuptake inhibitor (bupropion) on exercise performance, thermoregulation and neurotransmitters in the preoptic area and anterior hypothalamus (PO/AH) of the rat during exercise in the heat. Body core temperature (T(core)), brain temperature (T(brain)) and tail skin temperature (T(tail)) were measured. A microdialysis probe was inserted in the PO/AH, and samples for measurement of extracellular DA, NA and serotonin (5-HT) levels were collected. Rats received either bupropion (17 mg kg(-1); hot-BUP) or saline (1 ml kg(-1); hot) 20 min before the start of exercise and ran at a speed of 26 m min(-1) until exhaustion in a warm environment (30 degrees C). Rats also ran until exhaustion in a cool environment (18 degrees C; cool). Running time to exhaustion was significantly influenced by the ambient temperature, and it was increased by bupropion in the heat (cool, 143.6 +/- 21 min; hot, 65.8 +/- 13 min; hot-BUP, 86.3 +/- 7.2 min). T(core) and T(brain) at exhaustion were significantly higher in the bupropion group compared to the cool and hot groups, respectively. T(tail) measured at exhaustion was not significantly different between the two hot conditions. Extracellular concentrations of DA and NA in the PO/AH increased during exercise, and was significantly higher in the bupropion than in cool and hot groups (P < 0.05). No differences were observed between groups for 5-HT levels. These results suggest that DA and NA in the PO/AH might be responsible for the increase in exercise performance and T(core) and T(brain) in the bupropion group in hyperthermia. Moreover, these results support previous findings in humans that acute bupropion ingestion increases T(core) during exercise in the heat, indicating the possibility of an important role for DA and NA in thermoregulation.

Metabolic acidosis inhibits hypothalamic warm-sensitive receptors: a potential causative factor in heat stroke

the preoptic area and anterior hypothalamus (POAH) is regarded as the primary site for thermoreception in the mammalian brain. Peripheral thermal afferents synapse on temperature-sensitive neurons in the POAH. The POAH, in particular, contains a high concentration of warm-sensitive neurons, which

Ionic channels and conductance-based models for hypothalamic neuronal thermosensitivity

Thermoregulatory responses are partially controlled by the preoptic area and anterior hypothalamus (PO/AH), which contains a mixed population of temperature-sensitive and insensitive neurons. Immunohistochemical procedures identified the extent of various ionic channels in rat PO/AH neurons. These included pacemaker current channels [i.e., hyperpolarization-activated cyclic nucleotide-gated channels (HCN)], background potassium leak channels (TASK-1 and TRAAK), and transient receptor potential channel (TRP) TRPV4. PO/AH neurons showed dense TASK-1 and HCN-2 immunoreactivity and moderate TRAAK and HCN-4 immunoreactivity. In contrast, the neuronal cell bodies did not label for TRPV4, but instead, punctate labeling was observed in traversing axons or their terminal endings. On the basis of these results and previous electrophysiological studies, Hodgkin-Huxley-like models were constructed. These models suggest that most PO/AH neurons have the same types of ionic channels, but different levels of channel expression can explain the inherent properties of the various types of temperature-sensitive and insensitive neurons.

Point-Counterpoint: Heat-induced membrane depolarization of hypothalamic neurons: a putative/an unlikely mechanism of central thermosensitivity

heating and cooling various sites of the preoptic area and anterior hypothalamus (PO/AH) of mammals with fine thermodes reflexively evoke thermoregulatory responses, indicating that many central thermostats regulate temperature (T) of the brain ([16][1]). In PO/AH, heating- and cooling-activated

Effects of melatonin on thermally classified anterior hypothalamic neurons in the white-footed mouse ( Peromyscus leucopus)

1. The pineal hormone melatonin influences thermoregulation in many species, but the mechanism of action is unknown. 2. We tested whether melatonin could act directly on the primary thermoregulatory control center in the preoptic area and anterior hypothalamus (PO/AH), using a white-footed mouse tissue slice preparation. 3. PO/AH neurons were classified according to their thermosensitivity, then treated with 1 μM melatonin. 4. Thirty percent of warm-sensitive and 41% of temperature-insensitive neurons showed significant changes in firing rate during melatonin treatment. 5. While there was no correlation between responses to melatonin and thermosensitivity, these results constitute the first evidence that melatonin acts directly on PO/AH thermoregulatory neurons.

Acute dopamine/norepinephrine reuptake inhibition increases brain and core temperature in rats

The purpose of the present study was to examine the effects of an acute dose of the dual dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (Bup) on brain (T(brain)), body core (T(core)), and tail skin (T(tail)) temperature in freely moving rats and to simultaneously monitor the extracellular neurotransmitter concentrations in the preoptic area and anterior hypothalamus (PO/AH). A microdialysis probe was inserted in the PO/AH, and samples for NE, DA, and serotonin (5-HT) were collected every 20 min before and after the injection of 17 mg/kg of Bup, for a total sampling time of 180 min. T(core) was monitored using a biotelemetry system. T(brain) and T(tail), an index of heat loss response, were also measured. Both NE and DA levels in the PO/AH significantly increased after Bup injection compared with the baseline levels, reaching approximately 450 and 230%, respectively, 40 min after injection. There was no effect on 5-HT release. The neurotransmitter changes were accompanied by a significant decrease in T(tail) and an increase in both T(brain) and T(core) compared with the baseline levels. The present results demonstrate that inhibition of NE and DA reuptake suppresses heat loss mechanisms and elevates T(brain) and T(core) in freely moving rats.

Changes of body temperature and thermoregulatory responses of freely moving rats during GABAergic pharmacological stimulation to the preoptic area and anterior hypothalamus in several ambient temperatures

Action of γ-aminobutyric acid (GABA) in the preoptic area and anterior hypothalamus (PO/AH) has been implicated to regulate body temperature ( T b). However, its precise role in thermoregulation remains unclear. Moreover, little is known about its release pattern in the PO/AH during active thermoregulation. Using microdialysis and telemetry techniques, we measured several parameters related to thermoregulation of freely moving rats during pharmacological stimulation of GABA in normal (23 °C), cold (5 °C), and hot (35 °C) ambient temperatures. We also measured extracellular GABA levels in the PO/AH during cold (5 °C) and heat (35 °C) exposure combined with microdialysis and high performance liquid chromatography (HPLC). Perfusion of GABA A agonist muscimol into the PO/AH increased T b, which is associated with increased heart rate (HR), as an index of heat production in all ambient temperatures. Although tail skin temperature ( T tail) as an index of heat loss increased only under normal ambient temperatures, its response was relatively delayed in comparison with HR and T b, suggesting that the increase in T tail was a secondary response to increased HR and T b. Locomotor activity also increased in all ambient temperatures, but its response was not extraordinary. Interestingly, thermoregulatory responses were different after perfusion of GABA A antagonist bicuculline at each ambient temperature. In normal ambient temperature conditions, perfusion of bicuculline had no effect on any parameter. However, under cold ambient temperature, the procedure induced significant hypothermia concomitant with a decrease in HR in spite of hyperactivity and increase of T tail. It induced hyperthermia with the increase of HR but no additional change of T tail in hot ambient temperature conditions. Furthermore, the extracellular GABA level increased significantly during cold exposure. Its release was lower during heat exposure than in a normal environment. These results indicate that GABA in the PO/AH is an important neurotransmitter for disinhibition of heat production and inhibition of heat loss under cold ambient temperature. It is a neurotransmitter for inhibition of heat production under hot ambient temperature.

High Ambient Temperature Affects Exercise Performance, Thermoregulation And Hypothalamic Neurotransmitters During Exercise In The Rat

The attainment of a critically high brain and core temperature has been proposed as an important factor limiting endurance performance in the heat, and several neurotransmitters are thought to be involved in thermoregulation. The preoptic area and anterior hypothalamus (PO/AH), the center for thermoregulation are thought to responsible in controlling thermal and neurochemical homeostasis. However, until now no study has examined the effects of critical brain and core temperature on neurotransmitters during exercise. PURPOSE To investigate the relationship between exercise performance, thermal responses and brain neurotransmitters during exercise in the heat. METHODS Male Wistar rats were exercised for 2.5 wks on a treadmill. A telemetry device was implanted into the peritoneal cavity and two intracerebral guides were implanted under anesthesia. One guide was inserted in the left PO/AH for the microdialysis probe, and one in the right frontal cortex for thermocouple. On the day of the experiments, the microdialysis probe was connected to a microinjection pump and was perfused with a Ringer's solution at a flow rate of 1 μl/min. After 2 h of baseline collections, the animals were exercised at a speed of 26 m/min until exhaustion. One group ran in cool environment (18°C) another in warm environment (30°C). Time to exhaustion, noradrenaline (NA), dopamine (DA), and serotonin (5-HT) in the PO/AH, thermoregulatory responses (brain temperature: Tbrain, core temperature: Tcore, and Tail skin temperature: Ttail) were recorded prior to, during, and post exercise. RESULTS Exercise performance was significantly influenced by temperature (Cool: 147±17min, Warm: 73±5.7min). Thermal responses were not different between two conditions at the start of exercise, but the final temperatures of exercise in Warm were significantly higher than the Cool (Tbrain, Cool: 39.1±0.6°C, Warm: 40.7±0.6°C, Tcore, Cool: 39.9±0.4°C, Warm: 41.7±0.7°C, Ttail, Cool: 32.7±1.5°C, Warm: 35.7±1.1°C). Both NA and DA increased during exercise in both conditions, being lower in Warm than in Cool. No differences were observed between groups for 5-HT. CONCLUSIONS These results suggest that high ambient temperature influenced exercise performance not only via an increase in brain and core temperatures, but also because of a limitation in the heat loss mechanisms. DA and NA in the PO/AH might be responsible in the decrease in exercise performance observed in the heat. Supported by the Japan Society for the Promotion and Sciences and research council of the Vrije Universiteit Brussel (OZR990).

Inhibition of the preoptic area and anterior hypothalamus by tetrodotoxin alters thermoregulatory functions in exercising rats

We have previously demonstrated a functional role of the preoptic area and anterior hypothalamus (PO/AH) in thermoregulation in freely moving rats at various temperature conditions by using microdialysis and biotelemetry methods. In the present study, we perfused tetrodotoxin (TTX) solution into the PO/AH to investigate whether this manipulation can modify thermoregulation in exercising rats. Male Wistar rats were trained for 3 wk by treadmill running. Body core temperature (Tb), heart rate (HR), and tail skin temperature (Ttail) were measured. Rats ran for 120 min at speed of 10 m/min, with TTX (5 microM) perfused into the left PO/AH during the last 60 min of exercise through a microdialysis probe (control, n=12; TTX, n=12). Tb, HR, and Ttail increased during the first 20 min of exercise. Thereafter, Tb, HR, and Ttail were stable in both groups. Perfusion of TTX into the PO/AH evoked an additional rise in Tb (control: 38.2 +/- 0.1 degrees C, TTX: 39.3 +/- 0.2 degrees C; P <0.001) with a significant decrease in Ttail (control: 31.2 +/- 0.5 degrees C, TTX: 28.3 +/- 0.7 degrees C; P <0.01) and a significant increase in HR (control: 425.2 +/- 12 beats/min, TTX: 502.1 +/- 13 beats/min; P <0.01). These results suggest that the TTX-induced hyperthermia was the result of both an impairment of heat loss and an elevation of heat production during exercise. We therefore propose the PO/AH as an important thermoregulatory site in the brain during exercise.

Changes of body temperature and extracellular serotonin level in the preoptic area and anterior hypothalamus after thermal or serotonergic pharmacological stimulation of freely moving rats

Although many studies has been shown that serotonin (5-HT) in the preoptic area and anterior hypothalamus (PO/AH) is important for regulating body temperature (Tb), the exact role is not established yet due to conflicting results probably related to experimental techniques or conditions such as the use of anesthesia. The purpose of present study was to clarify the role of 5-HT in the PO/AH using the combined methods of telemetry, microdialysis and high performance liquid chromatography (HPLC), with a special emphasis on the regulation of Tb in freely moving rats. Firstly, we measured changes in Tb and levels of extracellular 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the PO/AH during cold (5°C) and heat (35°C) exposure. We also perfused fluoxetine (5-HT re-uptake inhibitor) and 8-hydroxy-2-(Di- n-propylamino)tetralin (8-OH-DPAT: 5-HT 1A agonist) into the PO/AH. During both exposures, although Tb changed significantly, no significant changes were noted in extracellular levels of 5-HT and 5-HIAA in the PO/AH. In addition, although perfusion of fluoxetine or 8-OH-DPAT into the PO/AH increased or decreased extracellular 5-HT and 5-HIAA levels in the PO/AH respectively, but Tb did not change at all. Our results suggest that 5-HT in the PO/AH may not mediate acute changes in thermoregulation.

Functional role of the preoptic area and anterior hypothalamus in thermoregulation in freely moving rats

We recently reported that perfusion of tetrodotoxin (TTX) into the preoptic area and anterior hypothalamus (PO/AH), by using a microdialysis technique, induced an increase in body temperature (Tb) under normal and hot ambient temperatures (23 and 35 °C) in freely moving rats. However, the procedure had no effect on Tb under a cold ambient temperature (5 °C). The present study was designed to determine the mechanism(s) of increases in Tb after perfusion of TTX into the PO/AH, by measuring tail skin temperature (Ttail) as an index of heat loss, and heart rate (HR) and locomotor activity (Act) as indexes of heat production, under three ambient temperatures. Under normal ambient temperature (23 °C), perfusion of TTX induced significant hyperthermia with increased HR, Act and Ttail. In a hot environment (35 °C), perfusion of TTX induced a greater increase in Tb with increased HR but no change in Ttail and Act. In a cold environment (5 °C), perfusion of TTX had no effect on Tb with a slight increase in Act but no change in HR and Ttail. Our results suggest that the PO/AH may be involved in inhibition of heat production and excitation/inhibition of the tail vasomotor tone.

Hypothalamic 11,12-epoxyeicosatrienoic acid attenuates fever induced by central interleukin-1β in the rat

Inhibitors of cytochrome P-450 augment fever in rats and mice, indicating that the metabolite of the enzyme is candidate of endogenous antipyretic. Cytochrome P-450 of arachidonic acid cascade leads to the formation of regioisomeric 5,6-, 8,9- 11,12- and 14,15-epoxyeicosatrienoic acid (EET). Various isomers of EET were administrated into the preoptic area and anterior hypothalamus (PO/AH) to test their influence on fever induced by interleukin-1β (IL-1β) administrated into the PO/AH in conscious rats. The IL-β-induced fever was attenuated in the 11,12-EET-pretreated rats, although 5,6-, 8,9- and 14,15-EET did not affect the fever. Intra-PO/AH injection of 11,12-EET did not alter normal body temperature. The results suggest that 11,12-EET acts in the hypothalamus as an endogenous antipyretic.

The role of preoptic area and anterior hypothalamus and median raphe nucleus on thermoregulatory system in freely moving rats

To clarify the role of the preoptic area and anterior hypothalamus (PO/AH) on thermoregulatory system and the effects of serotonergic innervation from the median raphe nucleus (MRN) on body temperature (Tb), we perfused tetrodotoxin (TTX) solution into the PO/AH or MRN by using a microdialysis technique at different ambient temperatures (5, 23 and 35°C) in freely moving rats. Tb was continuously monitored by using a telemetry system. In the MRN, perfusion of TTX solution induced significant hypothermia in the normal environment, a greater decrease in Tb during cold exposure and had no effect on Tb during heat exposure. In the PO/AH, perfusion of TTX solution induced significant hyperthermia in normal environment, a greater increase in Tb during heat exposure and had no effect on Tb during cold exposure. Our results indicate that the PO/AH regulates mainly heat loss or inhibits the loci regulating heat production. Furthermore, heat production appears to be regulated by other loci receiving serotonergic innervation from the MRN.

Inhibition of interleukin-1β and prostaglandin E 2 thermogenesis by glycyl-glutamine, a pro-opiomelanocortin-derived peptide

Interleukin-1β (IL-1β) and other cytokines produce fever by stimulating prostaglandin E 2 (PGE 2) synthesis in thermoregulatory regions of the preoptic area and anterior hypothalamus (POA/AH). Prostaglandin E 2 is thought to raise body temperature, at least in part, by stimulating β-endorphin release from pro-opiomelanocortin neurons that innervate the POA/AH. In this study, we investigated whether glycyl-glutamine (β-endorphin 30–31), an inhibitory dipeptide synthesized from β-endorphin post-translationally, inhibits IL-1β and PGE 2-induced hyperthermia. Hyperthermic sites were identified by microinjecting PGE 2 (3 fmol/1 μl) into the medial preoptic area (mPOA) of conscious, unrestrained rats. Interleukin-1β (1 U) injection into the same PGE 2 responsive thermogenic sites in the mPOA elicited a prolonged rise in colonic temperature ( T c) (+1.02±0.06°C) that persisted for at least 2 h. Glycyl-glutamine (3 nmol) co-injection into the mPOA inhibited IL-1β thermogenesis completely ( T c=−0.18±0.22°C). Glycyl-glutamine had no effect on body temperature when given alone to normothermic rats. Co-injection of individual amino acids, glycine and glutamine (3 nmol each amino acid), failed to influence IL-1β-induced thermogenesis, which indicates that Gly-Gln hydrolysis does not explain its inhibitory activity. Glycyl-glutamine (3 nmol) also prevented the rise in body temperature produced by PGE 2 (PGE 2=0.89±0.05°C; PGE 2 plus Gly-Gln=−0.16±0.14°C), consistent with evidence that PGE 2 mediates IL-1β-induced fever. These findings demonstrate that Gly-Gln inhibits the thermogenic response to endogenous pyrogens.