The vagus nerve in the thermoregulatory response to systemic inflammation

Abstract

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.

Effects of perineural capsaicin treatment of the abdominal vagus on endotoxin fever and on a non-febrile thermoregulatory event

“…17,19 This was supported by data obtained on rats pretreated with small i.p. doses of capsaicin: the febrile response was suppressed, presumably due to widePerivagal capsaicin and fever 263 spread damage of C-fibers of the abdominal cavity.…”

“…doses of bacterial LPS in rats (although fevers to large i.v. doses of LPS were not influenced), 17,18 while other authors found much stronger inhibition of fever by vagotomy in a different species. 19 The effects were explained by destruction of vagal afferent fibers that were presumed to carry information mainly from the liver, at which place LPS is preferentially detoxified.…”

Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

“…This interpretation is supported by the finding that in fluoxetine-treated rats, LPS-induced hyperthermia was facilitated in time and more pronounced during the initial few hours, but not at the later time points. LPS-induced hypothermia involves reduced thermogenesis by macrophagedependent , nonvagal (Romanovsky et al 1997) peripheral (Saper 1998) mechanisms. Several mediators have been proposed to be involved in LPSinduced hypothermia, including prostaglandins Wang et al 1997), leukotriens (Paul et al 1999), IL-10 (Leon et al 1999), TNF␣ and vasopressin Saper 1998).…”

Fever induction pathways: evidence from responses to systemic or local cytokine formation

“…Regarding the first question, it is possible that LPS when injected at high doses may leave the compartment (e.g., via circulation) and provoke systemic or local responses in other tissues. It must be remembered that in vagotomized rats the febrile effect of intraperitoneal LPS, mainly at high doses, is not always blocked (29) and that the pyrogen may induce fever when injected in other compartments of vagotomized animals. Using the Limulus amebocyte lysate assay we recently obtained evidence that, with the exception of few animals treated with a high LPS dose, LPS does not appear in the circulation of guinea pigs after its injection into the subcutaneous chamber.…”

“…Even the LPS-induced expression of the c-Fos and IL-1ß genes within the brain is depressed in vagotomized rats or mice (26,27). Suppression of LPS fever after vagotomy has been reported for guinea pigs (3,28) and rats (29), but this phenomenon seems to depend on the injected dose of LPS (29) and on the route of LPS administration (28). One study even reported that subdiaphragmatic vagotomy failed to cause a significant suppression of fever (30).…”