Effect of sympathetic blockade on central prostaglandin E2-induced hyperthermia

The mechanisms by which intracerebroventricular (i.v.t.) prostaglandin E2 (PGE2) produce hyperthermia in the rat were investigated. I.v.t. PGE2 produced dose-related increases in blood pressure, heart rate and rectal temperature which were significant with a dose of 0.5 ng. Oxygen consumption also increased and remained above baseline over an hour with 50 and 500 ng PGE2 doses. Ganglionic blockade with hexamethonium (20 mg/kg) attenuated the blood pressure and heart rate response to PGE2 but metabolic rate and rectal temperature increases were unchanged. Propranolol (2 mg/kg i.v.) decreased the heart rate response to PGE2 but had no significant effect on blood pressure, metabolic rate and rectal temperature responses. These results suggest a similar sensitivity of central receptors for mediating cardiovascular and metabolic rate/temperature increases but suggest that the mechanisms mediating these effects are separate.     

Specific binding of [H]prostaglandin E2 to rat brain membranes and synaptosomes

There is saturable, reversible and specific binding for [3H]prostaglandin E2 (PGE2) to rat brain membranes. This binding is of high affinity, selectively distributed with a maximum in the hypothalamus, the amygdala and the posterior pituitary, and is associated subcellularly with the synaptosomal fraction. This specific PGE2 binding has the characteristics expected for receptors, so opening new perspectives which might clarify the role of PGs in the brain.     

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 μg/kg, iv) or before PGE₂ microdialyzed into the POA (1 μg/μl at 2μl/min for 2.5 h) and during PGE₂ infused into a carotid artery (1 μg and 10 μg/μl at 2 μl/min for 1 h). LPS induced a biphasic 1.4°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 fover 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 substaintiates 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.     

Electroconvulsive therapy and plasma prostaglandin E2 metabolite in major depressive disorder

1. 1. Animal experiments show that PGE₂ affects the release of ACTH and corticosteroids. In depressed subjects, plasma concentrations of the same hormones are increased immediately following ECT. Consequently we explored passible effects of ECT on PGE₂.

2. 2. The major plasma PGE₂ metabolite (PGEM), ACTH, and cortisol were determined by RIA.

3. 3. PGEM did not change with time alone and anesthesia without ECT also did not have a consistent effect. PGEM was significantly elevated at all post ECT sampling times. The maximum increase, about fifty percent, was attained at 15 and 30 minutes. Similar changes were observed following ECT-I and ECT-VI.

4. 4. Positive correlations between PGEM, ACTH and cortisol were obtained.

5. 5. The results demonstrate that following ECT stimulus there is a robust increase in circulating PGEM. The increased release of PGE₂ may, in part, account for the elevated plasma ACTH and cortisol.

Circadian and Estral Changes in the Hypothalamic Prostaglandin E2 Content and [3H]Prostaglandin E2 Binding in Female Rats

Prostaglandin E₂, (PGE₂) is involved in the luteinizing hormone-releasing hormone-stimulated luteinizing hormone surge in female rats and may act via specific membrane receptors. The following studies were performed to determine whether there were any changes in the hypothalamic PGE₂ binding and/or PGE₂ content which were specific to proestrus and not to the rest of the estrous cycle. Groups of female Wistar rats were sacrificed at 3-h intervals throughout the estrous cycle to determine both the circadian and circaestral changes in the hypothalamic PGE₂ content and [³H]PGE₂ binding. The hypothalamic PGE₂ content was maximal at 1700 h on each of the 4 consecutive days of the estrous cycle but was independent of the stage of the cycle. [³H]PGE₂ binding also displayed a circadian rhythm; the lowest binding occurred near the circadian peak of PGE₂, suggesting that the PGE₂ binding sites were occupied by endogenous PGE₂. Since such circadian rhythms were not observed in the hypothalamus of male rats, they may be under the control of ovarian steroids. Also, since PGE₂ binding and the PGE₂ content both exhibit a diurnal pattern independent of the day of the cycle, there may be changes in the PGE₂ receptor-mediated process coupled to an adenylyl cyclase which could explain the luteinizing hormone surge in proestrus.     

Sensitization of group IV muscle receptors to bradykinin by 5-hydroxytryptamine and prostaglandin E2

The aim of the study was to find out whether endogenous substances with a presumed sensitizing action on nociceptors alter the chemical excitability of muscle receptors with unmyelinated afferent fibres. In anaesthetized cats, the discharges of single group IV units in response to intra-arterial injections of bradykinin were evaluated quantitatively and the influence of 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) on the response magnitude determined. Both 5-HT and PGE2 enhanced the bradykinin sensitivity of most of the muscle receptors, i.e. the receptors were sensitized to bradykinin by 5-HT and PGE2. Units that were activated by bradykinin before administration of the sensitizing chemicals showed an increase in response magnitude; in receptors not responding to the standard dose of bradykinin an activation often occurred after chemical sensitization. It is occurred that under the influence of elevated tissue levels of 5-HT and PGE2 the afferent impulse activity induced in group IV muscle receptors by bradykinin will be higher. As the substances used are released together from pathologically altered organs and since many of the group IV muscle receptors are considered to be nociceptive, the chemical sensitization of these receptors to the algesic agent bradykinin might play a role in the production of pain in an inflamed or injured muscle.     

Specific bindings of prostaglandin D2, E2 and F2α in postmortem human brain

Binding activities specific for each of [³H]prostaglandin (PG) D₂, E₂ and F_2α were detected in the P₂ fraction of the human brain homogenates. The bindings were time-dependent, saturable and of high affinity;K_dvalues were 30 nM for all the PG bindings. Regional distribution of these binding activities was determined by measuring specific bindings with 10 nM [³H]PG-D₂, [³H]PG-E₂ and [³H]PG-F_2α in the P₂ fractions from 17 brain regions. The PG-D₂ binding activity was high in the hypothalamus, amygdala and hippocampus followed by cerebellar nuclei, thalamus, nucleus accumbens and cerebral cortex. The PG-E₂ binding sites were similarly concentrated in the hypothalamus and the limbic system, but, unlike the PG-D₂ binding, no significant binding of [³H]PG-3₂ was observed in cerebellar nuclei, cerebellar cortex and putamen. Compared with these two PG bindings, PG-F_2α binding activity was low in many areas, but significant binding was detected in the amygdala, cingulate cortex, cerebellar medulla, hippocampus, nucleus accumbens, midbrain and hypothalamus. These results suggest the presence and specific distribution of three distinct types of PG binding activities, i.e. specific binding of PG-D₂, PG-E₂ and PG-F_2α, in the human brain.     

Changes in hypothalamic prostaglandin E2 may predict the occurrence of sleep or wakefulness as assessed by parallel EEG and microdialysis in the rat

Prostaglandin (PG) E₂ is produced by mammalian hypothalamus and when administered exogenously prolongs wakefulness. In order to study the relation of endogenous hypothalamic PGE₂ to sleep and wakefulness, we have used microdialysis in freely moving rats associated with EEG recording. Male Wistar rats were implanted with three cortical electrodes and with a guide cannula for microdialysis in the space between the paraventricular nucleus (PVN) and the ventromedial hypothalamus (VMH). PGE₂ was measured by RIA in 3-or 6-min dialysates 15 days after surgery, when sleep patterns were normal again and PGE₂ production stabilised. PGE₂ levels were significantly higher during wakefulness (601 ± 35 pg/ml, 5 experiments, 35 samples) than during slow-wave sleep (487 ± 24 pg/ml, 5 experiments, 49 samples). Samples corresponding to paradoxical sleep showed a tendency towards higher PGE₂ values compared to slow-wave sleep but lower compared to wakefulness. In epochs of wakefulness or sleep lasting at least 12 min, high PGE₂ levels in the middle of wakefulness regularly dropped, thus announcing the occurrence of sleep. During sleep, PGE₂ first went on dropping and then reincreased towards the values that characterize early periods of wakefulness. In its turn, this reincrease in PGE₂ announced the end of sleep and the imminent occurence of wakefulness. It is the first study to our knowledge showing that the evolvement in endogenous PG profile may predict the occurrence of sleep or wakefulness.     

Prostaglandin E1 inhibits calcium-dependent potentials in mammalian sympathetic neurons

Prostaglandin E1 (PGE1, 10-500 nM) reversibly depressed 3 types of calcium-dependent potentials associated with the spike potential of rabbit superior cervical ganglion cells, namely, the spike after-hyperpolarization, the post-tetanic hyperpolarization, and the Ca2+ spike evoked in a Na+-free/high Ca2+ solution. The results suggest that PGE1 reduces Ca conductance and that this action may underlie its inhibitory action on transmitter release at adrenergic and cholinergic nerve terminals.     

Role of the central muscarinic receptor of prostaglandin I2 in cardiovascular function in rat

The effects of injection of prostaglandin (PG) I2 into the cerebral ventricle on cardiovascular responses and their modification by intracerebroventricular (i.c.v.) pretreatment with several drugs were studied in male Wistar rats under urethane anesthesia. When injected into the ventricle, PG I2 (50 nmol/kg) caused a decrease in blood pressure and an increase in heart rate which were of short duration and were significantly inhibited by i.c.v. pretreatment with drugs, such as atropine (0.4 mumol/kg) and diphenhydramine (1 mumol/kg), having an anticholinergic effect. The similar effects induced by intravenous (i.v.) injection of PG I2 (5 nmol/kg) were not inhibited by i.v. pretreatment with these drugs. These results suggest that PG I2 play a role in regulation of cardiovascular function through central muscarinic acetylcholine receptors.     

Biphasic alteration in the trigeminal nociceptive neuronal responses after intracerebroventricular injection of prostaglandin E2 in rats

To investigate the role of prostaglandin E₂ (PGE₂) in the brain in nociception electrophysiologically, we injected PGE₂ (0.1 fmol–1 nmol) into the lateral cerebroventricle (LCV) of anesthetized rats and observed the changes of the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The LCV injection of PGE₂ at 1 fmol and 10 fmol enhanced the responses of the majority of WDR neurons to noxious stimuli, whereas that of PGE₂ at 100 pmol and 1 nmol suppressed them. The enhancement and suppression of the nociceptive responses of WDR neurons were observed 15–25 min and 5–15 min after injection of PGE₂ at 10 fmol (3.53 pg) and 1 nmol (353 ng), respectively. On the other hand, the LCV injection of PGE₂ at both 10 fmol and 1 nmol had no effect on the responses of the low threshold mechanoreceptive neurons to skin brushing. These results provide electrophysiological evidence that brain-derived PGE₂ has biphasic effects on nociception, i.e., it induces mechanical hyperalgesia at lower doses and hypoalgesia at higher doses in rats.     

Response of cyclic nucleotides to stimulation by prostaglandin E1 and 5-hydroxytryptamine in stored human platelets

Levels of cyclic nucleotides and their response to stimulation by prostaglandin E₁ (PGE₁) and 5-hydroxytryptamine were studied in human platelets stored for up to 48 hr at 22°C and 4°C. During storage at 22°C for 48 hr platelet cAMP levels declined gradually by approximately 20% while cGMP registered a 50% decrease. Levels of both cyclic nucleotides remained relatively stable in platelets stored at 4°C. Compared to prestorage controls 22°C stored platelets showed enhanced PGEl-stimulated cAMP production but had a depressed 5-HT-induced cGMP response. The latter was increased in 4°C stored platelets. Kinetic studies indicated that the enhanced PGE₁-stimulated cAMP production was due to an increase in the maximal capacity to produce cAMP while the depressed 5-HT-induced cGMP response was due to a decrease in the sensitivity to 5-HT of platelets stored at 22°C. Conversely,an increased sensitivity was responsible for the enhanced cGMP response to 5-HT stimulation in platelets stored at 4°C. These findings of our experiments are in accord with the documented changes in aggregability of stored platelets.     

Cyclic AMP independent inhibition of platelet aggregation by prostaglandin E1 is mediated through factor Xa

Normal plasma exposed to an insolublized ω-NH2-hexyl-agarose derivative of PGE₁ inhibits ADP-induced platelet aggregation. To define the plasma macromolecule responsible, we tested plasma congenitally deficient in coagulation factors for this property. Only plasma deficient in factor X failed to inhibit platelet aggregation under these conditions. The inhibition could be restored by reconstituting the defective plasma with bovine or human factor X. Purified factor X or Xa exposed to insolubilized PGE₁ also inhibited ADP-induced platelet aggregation. Factor Xa could reverse the inhibition of altered factor X but the reverse was not true suggesting that factor Xa was the responsible component. This conclusion was further supported by the ability of heparin to reverse the inhibitory effect of altered factor Xa when the anti-coagulant was added simultaneously to platelets. The results were not due to the release of PGE₁ from the insoluble derivative. Factor Xa may have a heretofore unrecognized effect on modulating platelet functions.     

Diencephalic sites responsive to prostaglandin E2 facilitation of sexual receptivity in estrogen-primed ovariectomized rats

Crystalline prostaglandin E₂ (PGE₂) induced high levels of sexual receptivity when stereotaxically implanted into the anterior-basal hypothalamic and preoptic regions of estrogen-primed, ovariectomized rats. Anterior- as well as medial basal hypothalamic implants of PGE₂ induced a significant elevation of rectal body temperature, but had no effect on open-field activity scores. The possibility that PGE₂ exerts its facilitatory effects upon sexual receptivity via an LHRH mechanism is discussed.     

Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats

To determine which prostaglandin E₂ (PGE₂) receptor subtypes are involved in the brain-derived PGE₂-induced changes in nociception, we injected synthetic EP₁, EP₂ and EP₃ receptor agonists (0.01 fmol to 10 nmol) into the lateral cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The enhancement and suppression of the nociceptive responses of the WDR neurons were observed after the LCV injection of MB28767 (an EP₃ receptor agonist) at a low dose range (1–100 fmol) and 17-phenyl-ω-trinor PGE₂ (an EP₁ receptor agonist) at high doses (1–10 nmol), respectively. Furthermore, the suppression of nociceptive neuronal responses after the LCV injection of PGE₂ (1 nmol) was completely blocked by SC19220 (an EP₁ receptor antagonist, 300 nmol). On the other hand, butaprost (an EP₂ receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl-ω-trinor PGE₂ (1 nmol), which respectively enhanced and suppressed the nociceptive neuronal responses, did not affect the responses of the low threshold mechanoreceptive neurons to innocuous tactile stimuli. These results provide electrophysiological evidence that brain-derived PGE₂ induces mechanical hyperalgesia and hypoalgesia through EP₃ and EP₁ receptors, respectively, in the rat.     

Awaking effect of prostaglandin E2 in freely moving rats

The awaking effect of prostaglandin (PG) E₂ was further examined in a long-term bioassay system. PGE₂ in saline solution was infused between 11.00 and 17.00 h at 0.1, 1, 10, and 100 pmol/min (infusion volume 10 μl/h) into the third cerebral ventricle of freely moving rats. These rats were otherwise infused with saline continuously and exhibited a circadian cycle, spending 70% of the daytime and 37% of the night in sleep. In the rats that received PGE₂ infusion at 1, 10 and 100 pmol/min, slow wave sleep (SWS) decreased to 84%, 69% and 71% and paradoxical sleep (PS) to 85%, 37% and 40% of the paired controls. Thus, the effect of PGE₂ was not specific to either SWS or PS. No effects were observed in the rats that received PGE₂ at 0.1 pmol/min. After PGE₂ infusion at 10 and 100 pmol/min, marked rebounds of both SWS and PS occurred during the night. SWS reduction by PGE₂ was due to the shortened duration of SWS episodes, while SWS increase in the rebound phase was due to the increased number of episodes. PS reduction was due to both the shortened duration and decreased number of PS episodes and PS rebound was due to both the prolonged duration and increased number of episodes. The circadian sleep-wake cycle returned to the baseline on the first or second recovery day after PGE₂ infusion. Sleep reduction by PGE₂ was accompanied by elevation of the brain temperature and rebound increase of sleep occurred with the fall of the brain temperature. On the basis of these findings, we conclude that PGE₂ has a central awaking effect without irreversible damage to the sleep-wake regulating mechanism and that the magnitude of the effect depends on the amount of PGE₂ at the site of action in the brain.     

Hypothalamic corticotrophin-releasing factor and norepinephrine mediate sympathetic and cardiovascular responses to acute intracarotid injection of tumour necrosis factor-alpha in the rat

Systemic administration of tumour necrosis factor (TNF)-α induces the release of norepinephrine in the paraventricular nucleus (PVN) of hypothalamus and an increase in expression of corticotrophin-releasing factor (CRF) and CRF type 1 receptors. We explored the hypothesis that CRF and norepinephrine in PVN mediate the cardiovascular and sympathetic responses to acute systemic administration of TNF-α. In anaesthetised rats, the increases in arterial pressure and heart rate induced by intracarotid artery injection of TNF-α were attenuated by intracerebroventricular (ICV) injection of either the α₁-adrenergic antagonist prazosin or the CRF antagonist α-helical CRF. Prazosin blocked the TNF-α-induced increase in renal sympathetic nerve activity (RSNA), whereas α-helical CRF substantially reduced the RSNA response. Conversely, CRF and the α₁-adrenergic agonist phenylephrine, administered ICV, both elicited increases in PVN neuronal activity, RSNA, arterial pressure and heart rate. Microinjection of CRF and phenylephrine directly into PVN evoked smaller responses. These results are consistent with the hypothesis that norepinephrine and CRF in the PVN mediate the cardiovascular and sympathetic responses to acute systemic administration of TNF-α.