Non-technical summary Systemic inflammation and related disorders, including sepsis, are leading causes of death in hospitalized patients. In most severe cases, systemic inflammation is accompanied by a drop in body temperature (hypothermia). We know that inflammation-associated hypothermia is a brain-mediated response, but mechanisms of this response are unknown. We administered a bacterial product (endotoxin) to rats to cause systemic inflammation and hypothermia. We then used a variety of pharmacological tools to probe whether three different receptors are involved in this hypothermia. We have found that one of the receptors studied, the so-called cannabinoid-1 (CB1) receptor, is crucial for the development of hypothermia. This is the same receptor that is responsible for many effects of marihuana (cannabis). We further show that hypothermia associated with inflammation depends on CB1 receptors located inside the brain. These novel findings suggest that brain CB1 receptors should be studied as potential therapeutic targets in systemic inflammation and sepsis.Abstract Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide (AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22• C, a moderate dose of LPS (25-100 μg kg −1 I.V.) induced a fall in body temperature with a nadir at ∼100 min postinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg −1 I.P.), by systemic TRPV1 antagonism with capsazepine (40 mg kg −1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kgHowever, CB1 receptor antagonism by rimonabant (4.6 mg kg −1 I.P.) or SLV319 (15 mg kgblocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant, the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEA did not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermoeffector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and thus to understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 μg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5000 μg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold-seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever–hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis and the other, previously unknown, that drives inflammation-associated cold seeking.SIGNIFICANCE STATEMENT Cold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold-induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH, a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders.

Rats respond to iv LPS with a complex thermoregulatory response, which is represented mostly by fever at a neutral Ta, but mostly by hypothermia at a subneutral Ta. Both the febrile and hypothermic components of this response are mediated by PGs, but the exact mechanism of the fever‐hypothermia switch is unknown. Wistar rats were injected with LPS (10, 100 or 1000 μg/kg iv) at a neutral (30°C) or subneutral (20°C) Ta. At 30°C, the febrile components of the response to each LPS dose were more pronounced; at 20°C, the hypothermic components were predominant. At either Ta, LPS caused a dose‐depended increase in plasma PGs within all five cascades (PGE2, D2, F2á, I2 and TXB2), whether measured by ELISA or LC/MS/MS. Irrespective of the method, we found no difference in the plasma response of any individual PG to any dose of LPS at 30°C vs 20°C. We then studied thermoregulatory responses of rats to iv PGs (0.8 μmol/kg, administered as albumin complexes) at 30 and 20°C. Only PGE2 caused a statistically significant fever, and this response was unaffected by Ta. Several PGs, including E2, D2 and I2, caused hypothermia, and this response was restricted to the subneutral conditions. We conclude that, regardless of Ta, LPS causes the same systemic PG response. The fever‐hypothermia switch involves LPS‐induced PGE2, D2 and I2 causing hypothermia in a subneutral (but not neutral) environment.Support: NS041233, NS064480, 11SDG4880051