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This study determined whether macrophage inflammatory protein-1beta (MIP-1beta) plays a role in the hyperthermia caused by prostaglandin E2 (PGE2) given intracerebroventricularly (i.c.v.) in the rat. In these experiments, anti-murine MIP-1beta antibody (anti-MIP-1beta) was micro-injected in the anterior hypothalamic, preoptic area (AH/POA) just before i.c.v. PGE2. The results showed that anti-MIP-1beta failed to alter the PGE2 hyperthermia. However, immunocytochemical studies revealed MIP-1beta immunoreactivity detectable in both the organum vasculosum laminae terminalis (OVLT) and AH/POA in the febrile rat. These data thus demonstrate that MIP-1beta is sequestered in diencephalic structures underlying thermoregulation even though it is not involved in PGE2 hyperthermia. This dissociation supports the viewpoint that at least two distinct systems exist in the brain which underlie a febrile response: MIP-1beta underlies one component whereas PGE2 comprises the other.

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1. The microinjection of macrophage inflammatory protein-1 (MIP-1 alpha; 5.0 and 25 pg) into the anterior hypothalamic, preoptic area (AHPOA) induced a slow onset; monophasic fever in rats that persisted for a long period. Microinjection of 25 pg MIP-1 beta into the AHPOA induced a fever of rapid onset, whereas 5.0 pg MIP-1 beta did not alter body temperature (Tb) significantly. When either MIP-1 alpha or MIP-1 beta was heated to 70 degrees C for 30 min prior to their injection, no pyrexic response was produced. 2. The concurrent microinjection of 25 pg MIP-1 alpha and 25 pg MIP-1 beta into the AHPOA attenuated the effects on Tb of either cytokine alone. However, pretreatment with either 5.0 pg MIP-1 beta or 5.0 pg MIP-1 alpha suppressed the febrile response induced by 25 pg MIP-1 alpha or 25 pg MIP-1 beta, given at the same site, respectively. 3. The present experiments show that MIP-1 alpha and MIP-1 beta are active individually and possess distinct differences in their evocation of a febrile response. Further, our results suggest a functional antagonism between MIP-1 alpha and MIP-1 beta that could represent a new level in the development of fever.

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Macrophage inflammatory protein-1 (MIP-1) evokes an intense fever, independent of a prostaglandin mechanism, and is now thought to play an important role in the defence response to bacterial pyrogens. The purpose of this study was 2-fold: (i) to determine whether the potent doublet of this cytokine, MIP-1beta, is actually produced in the brain in response to a pyrogenic dose of a lipopolysaccharide of Escherichia coli and (ii) to determine the anatomical site of synthesis of this cytokine in the brain. Following the intense fever produced by intraperitoneal administration of lipopolysaccharide in the unrestrained rat, MIP-1beta immunoreactivity was identified post mortem in two regions of the brain implicated in fever: the organum vasculosum laminae terminalis (OVLT) and the anterior hypothalamic, preoptic area (AH/POA). Microinjection of goat anti-mouse MIP-1beta antibody (anti-MIP-1beta) directly int the AH/POA markedly suppressed fever in rats in response to lipopolysaccharide. Further anti-MIP-1beta administered 180 min after the injection of lipopolysaccharide acted as an antipyretic and reversed the fever induced by the endotoxin. anti-MIP-1beta or control immunoglobulin G antibody microinjected into the hypothalamus immediately before the intraperitoneal injection of the control saline did not alter the temperature of the rats. Taken together, the present results demonstrate that MIP-1beta is produced in the brain in response to a bacterial endotoxin. These observations, in the light of earlier data on fever induced by MIP-1beta, further support the hypothesis that endogenously synthesized MIP-1beta acts as an intermediary factor in the evocation of fever by acting on the thermosensitive cells of the brain.

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The purpose of this study was to investigate the role of pyrogenic cytokines, such as IL-1 beta, IL-6 and MIP-1 beta, in the mechanisms underlying the hyperthermic response of rats to central injection of PGE2. Thus, specific murine neutralizing antibodies against these cytokines were micro-injected directly into the anterior hypothalamic, preoptic area (AH/POA) of unrestrained rats just before intracerebroventricular injection of PGE2. The significant hyperthermia induced by PGE2 was markedly suppressed by micro-injection of anti-IL-6 and partially attenuated by anti-IL-1 beta. However, the micro-injection of anti-MIP-1 beta failed to alter the hyperthermic response. The results indicate that PGE2-induced hyperthermia is presumably mediated through actions of IL-6 on the thermosensitive cells of the AH/POA and confirm that distinct and alternate pathways exist in the rat brain for the induction of fever.

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The purpose of this study was to clarify further the site of action in the amygdala as well as functional characteristics of feeding in response to two GABA receptor agonists. Guide cannulae for microinjection were implanted stereotaxically in the rat just above the central nucleus of the amygdala (CNA). Microinjections of 0.05, 0.25, 0.5 or 1.0 nmol muscimol, a GABAA-selective receptor agonist, produced a dose- and time-dependent decrease of food intake in both the satiated and fasted rat. The bilateral injection of muscimol into the amygdala was more effective than a unilateral injection during the first 2 h, although the overall effects were similar. Microinjection of 0.1 nmol bicuculline methiodide, a GABAA receptor antagonist, into the CNA significantly blocked this inhibitory effect of 0.05 and 0.5 nmol muscimol again in both the satiated and fasted rat. Doses of 0.05, 0.5, 5.0 and 10.0 nmol of the selective GABAB agonist, baclofen, injected into homologous sites in the CNA did not alter food intake. These findings support the viewpoint that the amygdala and its central nucleus comprise a pivotal region involved in the mechanisms underlying the control of feeding behavior. Further, it is envisaged that hypophagic or anorexic responses are induced through the activation of GABAA receptors by the presynaptic release of GABA from neurons which form a component of the anatomical system for hunger and satiety.

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The purpose of this study was to clarify the central site of action as well as functional characteristics of the febrile response of the cytokine, macrophage inflammatory protein-1 (MIP-1). Guide cannulae for microinjection were implanted stereotaxically in the rat just above the pyrogen and thermosensitive area of the anterior hypothalamic, preoptic area (AH/POA). Following postoperative recovery, the body temperature of each rat (Tbo) was monitored during an experiment by a colonic thermistor probe at 0.5-1.0-h intervals. When MIP-1 was microinjected in a 0.5-microliter volume into the AH/POA in one of eight concentrations ranging from 0.0028 nanograms (ng) to 9.0 ng, an intense monophasic or biphasic fever was evoked. The MIP-1-induced increase in the Tbo of the rat was characterized by its short latency of 15 to 30 min and an inverse dose-response curve. Measures of mean latency and maximal rise in Tbo following MIP-1 confirmed the potency of this dose. Although the dose of 0.028 ng produced a fever of over 2.0 degrees C with a latency of only 15 min or less, the hyperthermic response became less intense as the dose of MIP-1 was increased. An anatomical mapping of sites of microinjection which reacted to MIP-1 in mediating fever revealed that the medial portion of the POA of the rat just rostral to the border of the AH was the region of maximum sensitivity to the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)

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1. Intraperitoneal (i.p.) injection to restrained rats of GABA (250-1000 mg/kg) or the GABAA-receptor agonist muscimol (0.05-1 mg/kg) induced a dose-dependent decrease in body temperature (BT). 2. Intraperitoneal injection of low doses of the GABAB-receptor agonist (+/-)-baclofen (1-10 mg/kg) did not significantly affect BT. However, baclofen, at high doses (30 mg/kg), produced an increase in BT. 3. Pretreatment with either bicuculline (3 mg/kg) or naloxone (1 mg/kg) did not significantly modify the hypothermic response observed with GABA or muscimol, except for the high dose of GABA (1000 mg/kg) which was potentiated by bicuculline pretreatment. 4. Indomethacin pretreatment (5 mg/kg) significantly antagonized the hypothermia induced by GABA and muscimol. 5. Injection of baclofen alone (1 mg/kg) did not significantly affect BT, but in presence of the GABAA antagonist bicuculline, baclofen significantly decreased BT. 6. Baclofen-induced hyperthermia appear to be via prostaglandin and opioid mechanisms since both indomethacin and naloxone abolish this effect. 7. The hypothermia induced by GABA-agonists appears to be due to simultaneous activation of GABAA and GABAB receptors, while the hyperthermic effect of baclofen appears to be due to stimulation of GABAB receptors. 8. The present results suggest that involvement of prostaglandins in the effects of GABA, muscimol and baclofen, while endogenous opiates seem to be implicated only in baclofen induced hyperthermia. 9. It can be concluded that GABA may be involved in the control of BT through GABAA and GABAB receptors.

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Macrophage inflammatory protein (MIP-1) administered systemically causes a fever not blocked by a prostaglandin (PGE) synthesis inhibitor. The purpose of this study was to examine the central mechanism of pyrexic action of this cytokine in the unrestrained rat. After guide cannulae for microinjection were implanted stereotaxically just above the anterior hypothalamic preoptic area (AH/POA), the body temperature of each rat was monitored by a colonic thermistor probe. Saline control vehicle or MIP-1 was microinjected into the AH/POA in one of eight concentrations ranging from 0.0028-9.0 ng per 0.5 mu 1 volume. MIP-1 induced a biphasic or monophasic fever of short latency characterized by an inverse dose-response curve. The potency of MIP-1 was in the femtomolar (10(-15)) range with the lowest dose of 0.028 ng producing a fever of over 2.0 degrees C with a latency of 15 min or less. To determine whether a PGE mediates MIP-1 fever, indomethacin was administered either intraperitoneally in a dose of 5.0 mg/kg or directly into the MIP-1 injection site in a dose of 0.5 microgram/0.5 mu 1, both injected 15 min before MIP-1. Pretreatment of the injection site in the AH/POA with indomethacin failed to prevent the febrile response evoked by MIP-1 injected at the same locus. Further, the dose of systemic indomethacin, which blocks PGE-induced fever in the rat, attenuated only partially the MIP-1 fever. The results demonstrate that MIP-1 is the most potent endopyrogen discovered thus far, and that its action is directly in the region of the hypothalamus which contains both thermosensitive and pyrogen-sensitive neurons. The local action of MIP-1 on cells of the AH/POA in evoking fever is unaffected by the PGE inhibitor which indicates, therefore, that a cellular mechanism operates in the hypothalamus to evoke fever independently of the central synthesis of a PGE.

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The effects of gamma-aminobutyric acid (GABA), bicuculline and baclofen, orally and intraperitoneally (i.p.) administered, on the development of stress and pyloric ligation-induced gastric ulcers, were studied in rats. GABA, but not baclofen, significantly reduced the frequency and severity of both models as assessed by ulcer index, incidence and number of ulcers/animal. Gastric protection was dose-related in both experimental models and was completely antagonized by pretreatment with bicuculline methiodide, that blocks peripheral, but not central GABA receptors. All GABA effects were observed after oral and i.p. administration, but inhibition of gastric lesions was greater by the last route. Furthermore, GABA did not affect the acidity or the volume of gastric secretion in pylorus-ligated rats. Consequently its antiulcer activity appears to be mediated by factors unrelated to gastric acid secretion. Since the entry of GABA across blood-brain barrier is greatly restricted it may be concluded that stimulation of peripheral GABA receptors is primarily involved in its antiulcer action.

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gamma-Aminobutyric acid (GABA) intraperitoneally injected (i.p.) produced a dose-dependent hypothermia in restrained rats. GABA-induced hypothermia (1000 mg kg-1) was antagonized by pretreatment with atropine (2.5 and 10 mg kg-1 i.p.), hyoscine butylbromide (2.5 mg kg-1 i.p.), hexamethonium (0.75 mg kg-1 i.p.) or physostigmine (0.2 mg kg-1 s.c.). Hexamethonium (7.5 mg kg-1 i.p.) did not influence the hypothermia induced by GABA. The antagonism by physostigmine of GABA-induced hypothermia was attenuated by pretreatment of the rats with either alpha-methyl-p-tyrosine (200 mg kg-1 i.p.) or hexamethonium (7.5 mg kg-1 i.p.), but it was potentiated by either atropine (5 mg kg-1 i.p.) or hexamethonium (0.75 mg kg-1 i.p.). The data indicate that GABA-induced hypothermia may be partly mediated by acetylcholine release. Muscarinic receptors may play an important role in the effect of GABA. The results support the hypothesis of nicotinic presynaptic receptors modulating noradrenergic nerve endings that play a part in the hypothermic response of GABA.

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Gamma-aminobutyric acid (GABA) was injected intraperitoneally (i.p.) in conscious restrained rats and the effects on core temperature were observed. GABA (250-1000 mg/kg) produced a dose-dependent decrease in core temperature at an ambient temperature of 22 +/- 1 degree C. GABA-induced hypothermia (1000 mg/kg) was attenuated by pretreatment with reserpine (2 mg/kg, i.p.), p-chloro-phenyl-alanine (300 mg/kg, i.p.), yohimbine (0.25 mg/kg, i.p.) or methysergide (2.5 mg/kg, i.p.). Neither alpha-methyl-p-tyrosine (200 mg/kg, i.p.), nor phenoxybenzamine (5 mg/kg, i.p.), nor pimozide (0.5 mg/kg i.p.) antagonized GABA-induced hypothermia. Pretreatment with either propranolol (10 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) potentiated hypothermia induced by GABA. It is concluded that hypothermia produced by i.p. injection of GABA could be due to release of serotonin by activation of bicuculline-insensitive GABA receptors located on central serotonergic neurons.

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The anticonvulsant effect of compounds that inhibit peptidyl-dipeptidase (PDP) on bicuculline (BIC)- and strychnine (STRYC)-induced seizures was assessed after intracerebroventricular (ICV) or intraperitoneal (IP) administration in Swiss albino mice. STRYC-induced seizures were delayed by ICV injections and high IP doses of captopril, but not by ICV or IP injections of enalapril or by lower doses of captopril (0.1 mg/kg and 1 mg/kg IP). BIC-induced seizures were not suppressed by ICV or IP injections of either compound; on the contrary, captopril and enalapril exhibited proconvulsant effects when given IP or ICV by shortening the time of onset of tonic seizures and death. Results indicate that the anticonvulsant effect of captopril against STRYC-induced seizures is not mediated by central gamma-aminobutyric acid (GABA) receptors or by the inhibition of PDP.

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The effects of gamma-aminobutyric acid (GABA) on body temperature of restrained rats has been studied. GABA (250-1000 mg/kg i.p.) caused a dose-dependent fall in BT of restrained rats at an ambient temperature of 18-22 degrees C. The GABA-induced hypothermic response was attenuated by pretreatment with hexamethonium, p-chlorophenylalanine, methysergide, neostigmine and atropine (% MPE values: 27, 35, 51, 64 and 72 respectively). Pretreatment with methysergide and atropine was more potent than hexamethonium and methysergide in inhibiting the GABA-induced hypothermia (% MPE = 68 and 47 respectively). The antagonism by neostigmine of GABA-induced hypothermia was attenuated by pretreatment with hexamethonium (7.5 mg/kg). Yohimbine and chlorimipramine potentiated GABA hypothermia (% MPE = -82 and -8 respectively). The data indicate that GABA-induced hypothermia may be mediated by serotonin and acetylcholine release. Muscarinic receptors may play an important role in the effect of GABA. The results support the hypothesis that the hypothermia induced by GABA is modulated by nicotinic receptors.

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gamma-Aminobutyric acid (GABA) and sodium valproate (VPA) inhibit the formation of stress-induced gastric ulcers in guinea-pigs. The present study was conducted to evaluate the effect of these drugs on the development of cold- and restraint-induced gastric ulcers in guinea-pigs. In control saline-pretreated animals, a 3 h exposure to cold and restriction resulted in the production of gastric ulcers in 9 out of 10 animals. GABA (200 mg kg-1 oral, i.p.) completely prevented the development of gastric ulcers. VPA (100 and 200 mg kg-1 i.p.) exerted no significant effects on the development of gastric ulcers. GABA (100 mg kg-1 oral and i.p.) and VPA (oral) also exhibited partially protective activity. It is suggested that GABA may participate in a physiological modulation of the gastric mucosal barrier, by increasing its resistance to stress-induced lesions.

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GABA, delta-aminovaleric acid (DAVA) and sodium valproate (VPA) decrease core temperature in conscious rats. Bicuculline increases GABA-induced hypothermia, does not modify DAVA (250 mg/kg) and VPA (100 and 400 mg/kg) hypothermia and antagonizes initial hypothermia by DAVA (1000 mg/kg) and VPA (200 mg/kg) and late hypothermia by DAVA (500 mg/kg) and VPA (200 mg/kg). Picrotoxin increases late hypothermia by GABA (250 mg/kg) and VPA (400 mg/kg), but decreases initial hypothermia by VPA (200 mg/kg). Pentylenetetrazol increases variably GABA-induced hypothermia, inhibits early early hypothermia by DAVA and increases hypothermia induced by VPA (400 mg/kg). We conclude that GABA and GABA-agonists (DAVA and VPA) may induce hypothermia partly mediated by activation of bicuculline-insensitive GABA-receptors.

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