EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses

Lazarus, Michael; Yoshida, Kyoko; Coppari, Roberto; Bass, Caroline E.; Mochizuki, Takatoshi; Lowell, Bradford B.; Saper, Clifford B.

doi:10.1038/nn1949

Cited by 298 publications

(272 citation statements)

References 13 publications

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“…This early hyperthermia likely attenuates due to eventual desensitization at the postsynaptic alpha-1 ARs, the induction of COX-2 expression by activation of alpha-2 ARs, ensuing PGE 2 synthesis, and action at Prostaglandin E receptors (EP; presumably the EP 3 subtype) which contribute the late phase of fever (Feleder et al, 2007;Lazarus et al, 2007;Oka, 2004). The application of norepinephrine in the POAH has been shown to increase the frequency of spontaneous, miniature inhibitory postsynaptic currents (IPSCs) via the alpha-1 AR, and likewise decrease the frequency of IPSCs via the alpha-2 AR (Kolaj and Renaud, 2007).…”

Section: Discussionmentioning

confidence: 99%

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

et al. 2008

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Peripheral exposure to LPS induces a biphasic fever thought to be initiated via vagal afferents to the preoptic area of the anterior hypothalamus (POAH), an important thermoregulatory control center in the brain. Previous studies have shown norepinephrine synaptically mediates this Prostaglandin E 2 (PGE 2 )-dependent change in temperature through the selective activation of alpha-2 adrenoreceptors (AR). However, there is clear evidence that alpha-1 AR activation of thermoregulatory hypothalamic neurons will result in a rapid hyperthermia that is not dependent on PGE 2 . This direct action of norepinephrine in the POAH was tested in the present study by recording the single-unit activity of POAH neurons in a tissue slice preparation from the adult male rat, in response to temperature and the selective alpha-1 AR agonist Cirazoline (1−100 μM). Neurons were classified as either warm sensitive or temperature insensitive. Warm sensitive neurons responded to Cirazoline with a decrease in firing rate, while temperature insensitive neurons showed a firing rate increase. These responses are similar to those reported for PGE 2 and suggest that both warm sensitive and temperature insensitive neurons in the POAH are important in mediating this alpha-1 AR dependent hyperthermic shift in body temperature.

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Section: Discussionmentioning

confidence: 99%

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

et al. 2008

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“…To delete the loxP-flanked TD cassette and focally restore OX2R expression, OX2R TD mice were then injected with recombinant AAV-Cre (serotype 10) (33). With a glass micropipette and air pressure injector system, eight OX2R TD mice were injected with 50 nL (1.2 × 10 12 particles/mL) of AAV-Cre into the TMN region bilaterally (AP, −2.54 mm; 1.0 mm lateral; ventral, 4.9 mm from bregma).…”

Section: Methodsmentioning

confidence: 99%

Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

Mochizuki¹,

Arrigoni²,

Marcus

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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121

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Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wakepromoting effects of orexins, but orexins must stabilize sleep through other targets.arcolepsy is caused by a selective loss of the hypothalamic neurons producing the orexin (i.e., hypocretin) neuropeptides and is one of the most common causes of chronic sleepiness (1). In humans and mice, loss of orexin signaling results in unstable sleep/wake states, with poor maintenance of wakefulness, fragmented sleep, and intrusions into wakefulness of elements of rapid eye movement (REM) sleep, including brief episodes of paralysis known as cataplexy. The orexin neuropeptides strongly excite many brain regions that regulate sleep/wake behavior, yet the key pathways through which orexins stabilize wakefulness and sleep remain unknown.Orexins act through two receptors, OX1R and OX2R (also known as HCRTR1 and HCRTR2), and the OX2R seems to play a critical role in the maintenance of wakefulness. Mice constitutively lacking OX2R are unable to maintain long bouts of wakefulness and can fall asleep rapidly (2). In addition, an OX2R antagonist strongly promotes sleep, whereas an OX1R antagonist has no effect (3).Although it is clear that OX2R signaling is necessary for the normal maintenance of wakefulness, the anatomic sites through which this occurs remain unknown. OX2R is expressed in many wake-promoting brain regions, including the histaminergic neurons of the tuberomammillary nucleus (TMN), other monoaminergic regions, cholinergic systems, and forebrain regions, including the thalamus and cortex (4). Several researchers have hypothesized that the TMN is a key site because orexin-A excites the TMN neurons and infusion of orexin-A near this region promotes wakefulness (5-7). However, this perspective is controversial as optogenetic activation of the orexin neurons promotes arousal in mice lacking histamine (8), and mice lacking both OX1...

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“…Independently of its peripheral or cerebral origin, PGE 2 bind to a PGE 2 receptors on a specific group of neurons in the median preoptic nucleus (MnPO). Four subtypes of PGE 2 receptors have been described, namely EP1-EP4 (Oka, 2004), among which EP3 was shown to be critical in the induction of fever (Lazarus et al, 2007;Saper et al, 2012;Ushikubi et al, 1998). These EP3 receptor-bearing neurons are GABAergic neurons (Nakamura et al, 2002), which through neuronal projections inhibit the activity of neurons in dorsomedial nucleus of the hypothalamus (DMH) and rostral medullary raphe (rMR) (Nakamura, 2011).…”

Section: The Key Role Of Pgementioning

confidence: 99%

Behavioral fever in ectothermic vertebrates

Rakus

Ronsmans

Vanderplasschen

2017

Developmental & Comparative Immunology

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a b s t r a c tFever is an evolutionary conserved defense mechanism which is present in both endothermic and ectothermic vertebrates. Ectotherms in response to infection can increase their body temperature by moving to warmer places. This process is known as behavioral fever. In this review, we summarize the current knowledge on the mechanisms of induction of fever in mammals. We further discuss the evolutionary conserved mechanisms existing between fever of mammals and behavioral fever of ectothermic vertebrates. Finally, the experimental evidences supporting an adaptive value of behavioral fever expressed by ectothermic vertebrates are summarized.

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EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses

Cited by 298 publications

References 13 publications

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

The effects of Cirazoline, an alpha-1 adrenoreceptor agonist, on the firing rates of thermally classified anterior hypothalamic neurons in rat brain slices

Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

Behavioral fever in ectothermic vertebrates

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