Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis?

Abstract

Recent evidence has suggested a role of abdominal vagal afferents in the pathogenesis of the febrile response. The abdominal vagus consists of five main branches (viz., the anterior and posterior celiac branches, anterior and posterior gastric branches, and hepatic branch). The branch responsible for transducing a pyrogenic signal from the periphery to the brain has not as yet been identified. In the present study, we address this issue by testing the febrile responsiveness of male Wistar rats subjected to one of four selective vagotomies: celiac (CBV), gastric (GBV), hepatic (HBV), or sham (SV). In the case of CBV, GBV, and HBV, only the particular vagal branch(es) was cut; for SV, all branches were left intact. After the postsurgical recovery (26–29 days), the rats had a catheter implanted into the jugular vein. On days 29–32, their colonic temperature (Tc) responses to a low dose (1 μg/kg) of Escherichia colilipopolysaccharide (LPS) were studied. Three days later, the animals were subjected to a 24-h food and water deprivation, and the effectiveness of the four vagotomies to induce gastric food retention, pancreatic hypertrophy, and impairment of the portorenal osmotic reflex was assessed by weighing the stomach and pancreas and measuring the specific gravity of bladder urine, respectively. Stomach mass, pancreas mass, and urine density successfully separated the four experimental groups into four distinct clusters, thus confirming that each type of vagotomy had a different effect on the indexes measured. The Tc responses of SV, CBV, and GBV rats to LPS did not differ and were characterized by a latency of ∼40 min and a maximal rise of 0.7 ± 0.1, 0.6 ± 0.1, and 0.9 ± 0.2°C, respectively. The fever response of the HBV rats was different; practically no Tc rise occurred (0.1 ± 0.2°C). The HBV appeared to be the only selective abdominal vagotomy affecting the febrile responsiveness. We conclude, therefore, that the hepatic vagus plays an important role in the transduction of a pyrogenic signal from the periphery to the brain.

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

“…Antagonism of the alpha-1 ARs adds support for this observation, ultimately hindering rapid onset of fever and reducing its high point (Feleder, 2004). It has also been established that hepatic vagal afferents are necessary to promptly convey information from the immune system to the hypothalamus and initiate a fever in response to peripheral LPS exposure (Simons et al, 1998;MohanKumar et al, 2000). In this regard it appears that interleukin-1beta or PGE 2 stimulates the vagus (Li et al, 2006;Wieczorek and Dunn, 2006), and these noradrenergic pathways project from the brainstem through the ventral noradrenergic bundle and synapse in the POAH, where there are numerous noradrenergic terminals (Kumar et al, 2007).…”

Preoptic α1- and α2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs

“…Discounting, then, the possible, confounding effect of the acidity of the NE solution and assuming that the observed responses to coadministered cirazoline and clonidine represent those of buffered NE, we conjecture that the hypothermic effect of endogenous NE released in the POA in response to a peripheral stimulus, in contrast to exogenous NE microdialyzed continuously into the POA, could be masked whereas its simultaneously activated hyperthermic effects could be manifested and occur in succession, i.e., the first (cirazoline) rapid in onset, ␣ 1 -AR mediated and PGE 2 independent, and the second (clonidine) delayed, ␣ 2 -AR mediated and COX-2/PGE 2 dependent. If existent, such a mechanism could be pertinent to a postulated mechanism of the febrile response to peripheral LPS that posits that the pyrogenic message may be transmitted to the brain by vagal afferents, ultimately arriving in the POA via ascending noradrenergic projections (6,62,73). To wit, the febrile response of guinea pigs to intravenous LPS is characteristically biphasic, and COX-2 plays a greater role in the late than in the early phase of the fever (64).…”

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. In sham animals the vagus was isolated, but not cut.…”