Febrile responsiveness of vagotomized rats is suppressed even in the absence of malnutrition

Abstract

The repeatedly observed attenuation of fever in vagotomized rats has been accepted as evidence of an essential role of vagal afferents in the transduction of pyrogenic signals from the periphery to the brain. If, however, the general condition of a vagotomized animal is poor (the usual case) and accompanied by malnutrition and body mass loss (common complications of vagotomy), the febrile responsiveness can be suppressed not because of the lack of vagal afferentation, but rather secondarily to a malnutrition-associated thermogenic incompetence. In the present study, we addressed this dilemma. Male Wistar rats were subjected to subdiaphragmatic vagotomy (or sham surgery) and, 24 days later, catheterized in the jugular vein. Postsurgically, the rats were closely watched and fed highly palatable food. Their febrile responsiveness [colonic (Tc) and tail skin (Tsk) temperature responses] to Escherichia coli lipopolysaccharide (LPS: 1 microgram/kg i.v.) was tested on day 27 postvagotomy. To verify the completeness of vagotomy, each rat was food deprived for 24 h and then euthanized; its stomach's evacuatory function was assessed by weighing the organ. One month postsurgery, both food consumption and body mass of the vagotomized rats (33 +/- 2 g/day and 313 +/- 4 g, respectively) were similar to the control values (30 +/- 1 g/day and 315 +/- 8 g). In the sham rats, LPS induced a monophasic Tc rise of 0.5 +/- 0.3 degree C at 70 min postinjection (peak), preceded by a fall in Tsk. Neither this Tsk fall (tail skin vasoconstriction) nor the resultant fever occurred in the vagotomized rats; at 70 min, Tc change was -0.1 +/-0.1 degree C. The gastric mass (4.1 +/- 0.5 g in the vagotomized vs. 1.8 +/- 0.1 g in sham rats) indicated the effectiveness of vagotomy. In sum, although the vagotomy-associated malnutrition was successfully prevented with special perioperative care, the vagotomized animals still did not respond to LPS with fever. Malnutrition is, therefore, unlikely to constitute the main reason of the febrile irresponsiveness of vagotomized rats.

Bacterial Endotoxin Induces Fos Immunoreactivity in Primary Afferent Neurons of the Vagus Nerve

“…The substantial inhibition of Fos expression in vagotomized rats after intravenous LPS treatment suggests that intra-abdominal afferents constitute the major vagal afferents that respond to intravenous administration of this immune activator. These results are consonant with the results of Sehic and Blatteis [8] and Romanovsky et al [9], demonstrating that subdiaphragmatic vagotomy blocks febrile responses to low doses of intravenous LPS. These intra-abdominal afferents may thus relay both circulating and peritoneal immune signals.…”

“…Transection of the abdominal trunks of the vagus nerve in rats and mice abrogates brain-mediated illness responses to intraperitoneally administered bacterial endotoxin (lipopolysaccharide, LPS, constituents of gram-negative bacterial cell walls) and pro-inflammatory cytokines (interleukin-1ß, IL-1ß, and tumor necrosis factor-·), including hyperalgesia [1], hyperthermia [2], hypothalamus-pituitary-adrenal activation [3][4][5], social isolation, and food-motivated behaviors [6,7]. In addition, vagotomy inhibits thermogenic responses in guinea pigs and rats to intravenous LPS [8,9], supporting the possibility that the vagus nerve may also transmit blood-borne immune signals. Thus, the results from vagotomy studies suggest that immune-derived signals are carried by visceral sensory afferents of the vagus nerve to the brain, which then activates compensatory reflexes and coordinated neuroendocrine, autonomic, and behavioral defense mechanisms.…”

ANG II is involved in the LPS-induced production of proinflammatory cytokines in dehydrated rats

“…Actually, the IL-1␤ produced in response to ANG II may also stimulate afferent nerves, leading to the induction of fever. In fact, it has been found that the fever induced by intravenous injection of a low dose (1 g/kg) of LPS is inhibited by subdiaphragmatic vagotomy (21), suggesting the involvement of vagal afferents in the development of fever. More specifically, Romanovsky (20) noted in a review article that febrigenic chemical signals such as IL-1 originate in Kupffer cells and bind to appropriate receptors on the hepatic vagus, leading to fever induction.…”

Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways

“…Selective hepatic branch vagotomy, although not restricted only to liver (Phillips et al, 1997;Berthoud, 2004), circumvents much of the digestive and gastrointestinal dysfunction (Romanovsky et al, 1997bSimons et al, 1998) that accompanies total abdominal vagotomy (Louis-Sylvestre, 1983). Under ketamine:xylazine (85:15) anesthesia, the abdomen was opened, and the hepatic branch of the vagus was located as previously described (Simons et al, 1998;Warne et al, 2007) and cut.…”