Genesis of biphasic thermal response to intrapreoptically microinjected clonidine

Romanovsky, Andrej A.; Shido, O.; Ungar, A. L.; Blatteis, Clark M.

doi:10.1016/0361-9230(93)90117-t

Cited by 25 publications

(16 citation statements)

References 13 publications

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“…In support, the late hyperthermic response to clonidine microinjected intracerebroventricularly into conscious mice is suppressed in COX-2 gene-ablated animals (unpublished observation). Although we have previously observed a biphasic hypo-/hyperthermic response to intra-POA microinjected (rather than microdialyzed) clonidine (55), in that study in contrast to the present one, the ␣ 2 -AR antagonist rauwolscine microinjected 10 min before clonidine abolished the hypothermia without affecting the subsequent hyperthermia; the latter was attenuated by the intramuscular injection of the nonspecific COX inhibitor indomethacin 20 min after the intra-POA microinjection of clonidine. This response was similar to that to dibutyryl-cAMP reported by Dascombe (11,12).…”

Section: Discussioncontrasting

confidence: 93%

“…We interpreted those data as verifying the ␣ 2 -AR-mediated hypothermic action of clonidine and, like Dascombe, attributed the subsequent T c rise to contamination of the thermal response to this agonist by PGE 2 released in the POA consequent to the acute inflammatory response to the microinjection procedure per se (57). However, in view of the present findings, we now suggest that the late reduced hyperthermic response to microinjected clonidine observed in that previous study (55) was also partly accomplished by ␣ 2 -ARmediated, as contrasted only to injury-induced, upregulation of COX-2-dependent PGE 2 .…”

Section: Discussionsupporting

confidence: 84%

“…Clonidine has consistently been reported to evoke T c falls when microinjected intra-POA in various species (39,55). In our own previous studies (50,51), it also induced dosedependent T c falls in conscious guinea pigs when microdialyzed intra-POA for 3 h at doses from 0.5 to 10 g/l.…”

Section: Discussionsupporting

confidence: 53%

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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Feleder, Carlos, Vit Perlik, and Clark M. Blatteis. Preoptic ␣1-and ␣2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs. Am J Physiol Regul Integr Comp Physiol 286: R1156 -R1166, 2004. First published February 12, 2004 10.1152/ajpregu.00486.2003We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE2 release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE2 and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (␣1-AR agonist), and clonidine (␣2-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (Tc) and intra-POA PGE2 responses. Cirazoline induced Tc rises promptly after the onset of its dialysis without altering PGE2 levels. NE and clonidine caused early falls followed by late rises of Tc; intra-POA PGE2 levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced Tc and PGE2 falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine-and NE-induced Tc and PGE2 rises. Coinfused cirazoline and clonidine reproduced the late Tc rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE2 responses were similar to those to NE. Prazosin (␣1-AR antagonist) and yohimbine (␣2-AR antagonist) blocked the effects of their respective agonists. These results indicate that ␣1-and ␣ 2-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct Tc responses: ␣1-AR activation produces quick, PGE2-independent T c rises, and ␣2-AR stimulation causes an early Tc fall and a late, COX-2/PGE2-dependent Tc rise. thermoregulation; cyclooxygenase inhibitors; prostaglandin E 2; noradrenergic agonists and antagonists; care temperature; norepinephrine THERE IS MUCH EVIDENCE that norepinephrine (NE) and prostaglandin (PG) E 2 interact in many tissues, including nervous tissue (33). For example, an intimate association between NE and PGE 2 is well documented in the peripheral nervous system (21); to wit, the stimulation of sympathetic neurons induces the postsynaptic release of PGE 2 , which then limits the further presynaptic release of NE, thereby modulating the activity of noradrenergic neurons. It is also well documented that NE induces PGE 2 synthesis in brain tissue (23, 60) where its feedback inhibition of the presynaptic release of NE has been similarly documented (3,13,54).In conscious guinea pigs, NE microinjected into the preoptic-anterior hypothalamic area [POA, the locus of the thermal controller (7)] evokes body (core) temperature (T c ) rises (75,47). Electrical stimulation of the ascending noradrenergic system in the brain stem yields the same result (67), whereas chemical sympat...

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Section: Discussioncontrasting

confidence: 93%

Section: Discussionsupporting

confidence: 84%

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The hyperthermia observed in the present experiments and the elevated body temperatures reported by Blatteis et al (5,6) and Hunter et al (26) clearly differ from the acute fevers that often occur in response to preoptic hypothalamic tissue damage (13,35,53,56). Such acute fevers are relatively short lasting and resolve within a few days (6,35).…”

Section: Hyperthermia Induced By Ovlt Lesioncontrasting

confidence: 54%

“…Such acute fevers are relatively short lasting and resolve within a few days (6,35). They are thought to involve migration of leukocytes to the site of damage, local hemorrhage, and inflammation (13) and to be mediated by pyrogenic cytokines (35) and PGs (53,56).…”

Section: Hyperthermia Induced By Ovlt Lesionmentioning

confidence: 99%

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

Romanovsky

Sugimoto²,

Simons³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Romanovsky, Andrej A., Naotoshi Sugimoto, Christopher T. Simons, and William S. Hunter. The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments. Am J Physiol Regul Integr Comp Physiol 285: R420-R428, 2003. First published April 24, 2003 10.1152/ajpregu.00757. 2002The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many "side effects" not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by ϳ2°C) and long-lasting (Ͼ3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1␤ (500 ng/kg iv) was tested. The shamoperated rats developed typical monophasic fevers (ϳ0.5°C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39-40°C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain. fever; adipsia; third ventricle; median preoptic nucleus THERE IS LITTLE DOUBT that the febrile response is regulated by the central nervous system (CNS), but the mechanisms by which peripherally originating pyrogenic signals reach the brain remain unclear. At least four possibilities have been proposed. First, pyrogenic cytokines, such as IL-1␤, access the CNS by carriermediated transport across the blood-brain barrier (BBB) (2). Second, circulating pyrogens bind to the cerebral vascular endothelium and stimulate production of fever mediators, most importantly PGE 2 , by endothelial cells; endotheliocytes release PGE 2 into the brain tissue (10). Third, pyrogens act on neural terminals in peripheral tissues and convey febrigenic signals to the CNS via sensory fibers, e.g., those of the vagus nerve (7, 74). Fourt...

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Antipyretic Effect of Clonidine in Intensive Care Unit Patients: A Nested Observational Study

Mokhtari

Sistanizad

Farasatinasab

2016

The Journal of Clinical Pharma

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Fever in the intensive care unit (ICU) is usually an adaptive response to infection or inflammation. Pharmacological intervention is often required in addition to addressing the underlying causes of fever. Animal studies have examined the antipyretic effect of clonidine; however, to our knowledge there are no clinical data available in humans. The observation of an antipyretic effect of clonidine was made during a single-center randomized control trial that was designed to study the effect of clonidine addition to the commonly used sedative agents in mechanically ventilated ICU patients. Forty patients 18 years or older on mechanical ventilation for 3 days or longer were randomized into 2 groups receiving clonidine and placebo. In addition to the usual sedation/analgesia, patients in the clonidine arm received enteral clonidine in doses of 0.1 mg 3 times a day (TID), which was increased to 0.2 mg TID if the hemodynamics remained stable. Vital signs, laboratory data, all cultures, and daily ICU events were recorded. The odds ratio of temperature higher than 38.3°C was 3.96 times higher in the placebo group, after adjustment for the illness severity and the time of follow-up (P = .049). A lower temperature (0.52°C) was observed in the clonidine group after adjustment for the time of follow-up (P = .006). Our report is the first of its kind in humans that demonstrates possible antipyretic properties of enteral clonidine in the critically ill intensive care unit patient.

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Genesis of biphasic thermal response to intrapreoptically microinjected clonidine

Cited by 25 publications

References 13 publications

Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

Antipyretic Effect of Clonidine in Intensive Care Unit Patients: A Nested Observational Study

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Genesis of biphasic thermal response to intrapreoptically microinjected clonidine

Cited by 25 publications

References 13 publications

Preoptic α1- and α2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs

Preoptic α1- and α2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

Antipyretic Effect of Clonidine in Intensive Care Unit Patients: A Nested Observational Study

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs