Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Székely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.

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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.

1 As pretreatment with intraperitoneal capsaicin CAP), an agonist of the vanilloid receptor known as VR1 or transient receptor potential channel-vanilloid receptor subtype 1 (TRPV-1), has been shown to block the first phase of lipopolysaccharide (LPS) fever in rats, this phase is thought to depend on the TRPV-1-bearing sensory nerve fibers originating in the abdominal cavity. However, our recent studies suggest that CAP blocks the first phase via a non-neural mechanism. In the present work, we studied whether this mechanism involves the TRPV-1. 2 Adult Long-Evans rats implanted with chronic jugular catheters were used. 3 Pretreatment with CAP (5 mg kg À1 , i.p.) 10 days before administration of LPS (10 mg kg À1 , i.v.) resulted in the loss of the entire first phase and a part of the second phase of LPS fever. 4 Pretreatment with the ultrapotent TRPV-1 agonist resiniferatoxin (RTX; 2, 20, or 200 mg kg À1 , i.p.) 10 days before administration of LPS had no effect on the first and second phases of LPS fever, but it exaggerated the third phase at the highest dose. The latter effect was presumably due to the known ability of high doses of TRPV-1 agonists to cause a loss of warm sensitivity, thus leading to uncontrolled, hyperpyretic responses. , i.p.) did not affect LPS fever, but blocked the immediate hypothermic response to acute administration of CAP. 6 It is concluded that LPS fever is initiated via a non-neural mechanism, which is CAP-sensitive but RTX-and CPZ-insensitive. The action of CAP on this mechanism is likely TRPV-1-independent. It is speculated that this mechanism may be the production of prostaglandin E 2 by macrophages in LPSprocessing organs.