Cold‐seeking behavior as a thermoregulatory strategy in systemic inflammation

Abstract

Systemic inflammation (SI) is a leading cause of hospital death. Although fever and hypothermia are listed as symptoms in every definition of SI, how SI affects thermoregulatory behavior is unclear. SI is often modeled by systemic administration of bacterial lipopolysaccharide (LPS) to rats. When rats are not allowed to regulate their body temperature (Tb) behaviorally, LPS causes either fever or hypothermia, and the direction of the response is determined by LPS dose and ambient temperature (Ta). However, in many studies in which rats were allowed to regulate Tb behaviorally (by selecting their preferred Ta in a thermogradient apparatus), they consistently expressed warmth-seeking behavior and developed fever. We hypothesized that SI can cause not only warmth-seeking behavior but also cold-seeking behavior; we then tested this hypothesis by studying LPS-induced thermoregulatory behavior in adult Wistar rats. A multichannel thermogradient apparatus, implantable data loggers and infrared thermography were used; multiple control experiments were conducted; and the ability of the apparatus to reliably register the changes in rats' preferred Ta induced by thermal (external cooling or heating) or chemical (TRPV1 or TRPM8 agonist) stimuli was confirmed. The rats responded to a low dose of LPS (10 microg/kg i.v.) with warmth-seeking behavior and a polyphasic fever, but to a high dose (5 mg/kg i.v.) with marked cold-seeking behavior and hypothermia followed by warmth-seeking behavior and fever. This is the first well-controlled study to report SI-associated cold-seeking behavior in rats. Cold-seeking behavior is likely to be an important defense response in severe SI.

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

“…It is well known that experimental animals, including rats and mice, respond to vanilloid agonists such as capsaicin and RTX with a fall in T b (Dogan et al, 2004;Almeida et al, 2006b). The hypothermic action of these compounds is known to result from pharmacological activation of the TRPV1 channel (Caterina et al, 2000;Dogan et al, 2004;Shimizu et al, 2005).…”

“…The six-channel thermogradient apparatus used has been described in detail previously (Almeida et al, 2006b). Each rat was allowed to move freely inside a long aluminum channel that had a linear T a gradient (15-30°C).…”

Intragastric Administration of TRPV1, TRPV3, TRPM8, and TRPA1 Agonists Modulates Autonomic Thermoregulation in Different Manners in Mice

“…[16][17][18][19] As behavioral thermoregulation, resiniferatoxin causes rats to select cool temperatures in a multichannel thermogradient setup. 20) These results suggest that the TRPV1 channel is involved in both autonomic and behavioral thermoregulation. Hence other thermosensitive TRPs (thermoTRPs) might also play a role in the detection of peripheral temperature and the control of core temperature.…”

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

“…At a subneutral T a (cool environment), hypothermia followed by fever is the predominant response; the magnitude of the hypothermia increases along with the LPS dose (9, 52, 70). Our studies show that LPS-induced fever and hypothermia are both physiological responses brought about by brain-driven changes in thermoeffector activity (3,4,70). Whereas the biological value of fever is thought to be related to its immunostimulant and antibacterial effects (43), the biological value of hypothermia may be related to energy conservation when inflammation is severe enough to compromise tissue perfusion or threaten energy reserves (72, 82).…”