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

Abstract

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...

Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense Effectors

“…This hypothesis agrees with the fact that the anterior preoptic hypothalamus (that contains the OVLT) is more important for the control of autonomic thermoeffectors than for the control of thermotaxis (Almeida et al, 2006a) and with the fact that electrolytic lesions of the OVLT and neighboring structures readily cause hyperthermia (Romanovsky et al, 2003). We found, however, that AMG0347 fails to cause marked hyperthermia when infused via the route (intracerebroventricular) that provides good access to the OVLT and other circumventricular structures.…”

Lesions of the anteroventral third ventricle region exaggerate neuroendocrine and thermogenic but not behavioral responses to a novel environment

“…Basal thermoregulation was unaffected by the AV3V lesion. This is in contrast to a recent report in which similar lesions were found to produce a prolonged (Ͼ3 wk) hyperthermia (ϳ2°C) (26). Although we did not measure circadian temperature rhythms in these animals, T C did not differ between sham-and AV3V-lesion rats in the 30 min before exposure to the novel environment, nor was there any difference in the colonic temperature of the rats that remained in their home cage throughout protocol 2.…”

“…Romanovsky et al (26) suggested that destruction of the AV3V region may eliminate warm-sensitive neurons within the MnPO responsible for the inhibition of thermogenesis. It is therefore possible that our slightly larger lesions restored the balance between thermolytic and thermogenic pathways in some manner.…”

“…Levels of Fos activity are elevated in the AV3V region after restraint stress (34); however, Hunter (14) found that AV3V lesions had no impact on stress-induced fever. More recently, Romanovsky et al (26) found that electrolytic lesions of this region resulted in a prolonged hyperthermia that lasted upward of 3 wk. In contrast to both of these lesion studies, we have previously reported that AV3V-lesion animals produce an exaggerated stress-induced fever in response to gentle handling (35,37).…”

“…Fos-like immunoreactivity is elevated in the AV3V region after intravenous LPS administration (8) and injection of IL-1␤ into this region produces fever (29). Conversely, LPS-induced fever is attenuated by ablation (3,5,14) or injection of cyclooxygenase inhibitors into the AV3V region (30), although the former result has recently been challenged (26). Whether the AV3V region is also involved in psychological or stress-induced fever is less apparent.…”