Our body temperature is normally kept within a narrow range of 1°C. For example, if our body temperature rises, such as in a hot environment or due to strenuous exercise, our thermoregulatory system will trigger a powerful heat defense response with vasodilation, sweating, and lowered metabolism. During fever, which often involves body temperatures of up to 41°C, this heat defense mechanism is apparently inhibited; otherwise, the rising body temperature would be immediately combated, and fever would not be allowed to develop. New evidence suggests how and where this inhibition takes place. In two consecutive studies from Cheng et al. and Xu et al., it has been shown that prostaglandin E2, which generates fever by acting on thermosensory neurons in the preoptic hypothalamus, also acts on neurons in the brainstem parabrachial nucleus, which receive temperature information from temperature-activated spinal cord neurons and relay this information to the thermoregulatory center in the hypothalamus to either induce cold or heat defenses. By acting on the same type of prostaglandin E2 receptor that is critical for fever generation in the preoptic hypothalamus, the EP3 receptor, prostaglandin E2 inhibits the signaling of the heat-responsive parabrachial neurons, while stimulating the cold-responsive neurons. These novel findings thus show that prostaglandin E2, by binding to the same receptor subtype in the parabrachial nucleus as in the preoptic hypothalamus, adjusts the sensitivity of the thermosensory system in a coordinated manner to allow the development of febrile body temperatures.

Anorexia is a common symptom during infectious and inflammatory disease. Here we examined the role ofmelanocortin-4 receptors (MC4Rs) in inflammation-induced anorexia. Mice with transcriptional blockage of theMC4Rs displayed the same reduction of food intake following peripheral injection of lipopolysaccharide as wildtype mice but were protected against the anorexic effect of the immune challenge in a test in which fastedanimals were to use olfactory cues to find a hidden cookie. By using selective virus-mediated receptor reexpression we demonstrate that the suppression of the food-seeking behavior is subserved by MC4Rs in thebrain stem parabrachial nucleus, a central hub for interoceptive information involved in the regulation of foodintake. Furthermore, the selective expression of MC4R in the parabrachial nucleus also attenuated the bodyweight increase that characterizes MC4R KO mice. These data extend on the functions of the MC4Rs and showthat MC4Rs in the parabrachial nucleus are critically involved in the anorexic response to peripheral inflammation but also contribute to body weight homeostasis during normal conditions. 

The initiation of fever has been a matter of controversy. Based on observations of little or no induction of prostaglandin synthesizing enzymes in the brain during the first phase of fever it was suggested that fever is initiated by prostaglandin released into the circulation from cells in the liver and lungs. Here we show in the mouse that prostaglandin synthesis is rapidly induced in the brain after immune challenge. These data are consistent with our recent findings in functional experiments that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of all phases of fever.

Fever is known to be elicited by prostaglandin E2 acting on the brain, but its origin has remained disputed. We show in mice that selective deletion of prostaglandin synthesis in brain endothelial cells, but not in neural cells or myeloid cells, abolished fever induced by intravenous administration of lipopolysaccharide and that selective rescue of prostaglandin synthesis in brain endothelial cells reinstated fever. These data demonstrate that prostaglandin production in brain endothelial cells is both necessary and sufficient for eliciting fever. 

Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio. (C) 2020 The Author(s). Published by Elsevier Masson SAS.

Experimental autoimmune encephalomyelitis (EAE) is the most common model for studying the molecular mechanisms of multiple sclerosis (MS). Here, we examined the CNS-restricted effects of classical interleukin (IL)6 signaling on the development of EAE, using mice with cell-type specific deletion of the IL-6 receptor (IL-6R). We found that IL-6R deletion in CNS vascular endothelial cells, but not in microglia, ameliorated symptoms of EAE. The milder clinical symptoms in the gene-deleted mice were associated with less demyelination and immune cell infiltration/activation, and lower mRNA levels of the cytokines IL-17 and IL-1 beta, as well as the cell adhesion molecules VCAM-1, ICAM-1 and ICAM-2 than what was seen in WT mice. These findings demonstrate that classical IL-6 signaling via endothelial cells of the CNS contributes substantially to the development of MS-like pathology, which should be taken into consideration when conceptualizing future therapeutic approaches.

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8–9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E-2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E-2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E-2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E-2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.