Lipopolysaccharide fever is initiated via a capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

Abstract

As pretreatment with intraperitoneal capsaicin (8-methyl-N-vanillyl-6-nonenamide, 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. Adult Long-Evans rats implanted with chronic jugular catheters were used. Pretreatment with CAP (5 mg kg(-1), i.p.) 10 days before administration of LPS (10 microg kg(-1), i.v.) resulted in the loss of the entire first phase and a part of the second phase of LPS fever. Pretreatment with the ultrapotent TRPV-1 agonist resiniferatoxin (RTX; 2, 20, or 200 microg kg(-1), 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. Pretreatment with the selective competitive TRPV-1 antagonist capsazepine (N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamidem, CPZ; 40 mg kg(-1), i.p.) 90 min before administration of LPS (10 microg kg(-1), i.v.) or CAP (1 mg kg(-1), i.p.) did not affect LPS fever, but blocked the immediate hypothermic response to acute administration of CAP. 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 LPS-processing organs.

Figure 1

Effects of pretreatment with CAP (5 mg kg⁻¹, i.p.) or vehicle on the following responses: the body temperature response to LPS (10 μg kg⁻¹, i.v.) or saline (a); the relative difference in the amount of food consumed by food-deprived rats during a 30-min period after administration of CCK-8 sulfate (6 μg kg⁻¹, i.p.) or saline (b); and the number of eye wipes during a 30-s period after intraocular administration of a drop of 1% NH₄OH (c).

Figure 2

Effects of pretreatment with RTX (2 μg kg⁻¹, i.p.) or vehicle on the following responses: the body temperature response to LPS (10 μg kg⁻¹, i.v.) or saline (a); the relative difference in the amount of food consumed by food-deprived rats during a 30-min period after administration of CCK-8 sulfate (6 μg kg⁻¹, i.p.) or saline (b); and the number of eye wipes during a 30-s period after intraocular administration of a drop of 1% NH₄OH (c).

Figure 3

Effects of pretreatment with RTX (20 μg kg⁻¹, i.p.) or vehicle on the following responses: the body temperature response to LPS (10 μg kg⁻¹, i.v.) or saline (a); the relative difference in the amount of food consumed by food-deprived rats during a 30-min period after administration of CCK-8 sulfate (6 μg kg⁻¹, i.p.) or saline (b); and the number of eye wipes during a 30-s period after intraocular administration of a drop of 1% NH₄OH (c).

Figure 4

Effects of pretreatment with RTX (200 μg kg⁻¹, i.p.) or vehicle on the following responses: the body temperature response to LPS (10 μg kg⁻¹, i.v.) or saline (a); the relative difference in the amount of food consumed by food-deprived rats during a 30-min period after administration of CCK-8 sulfate (6 μg kg⁻¹, i.p.) or saline (b); and the number of eye wipes during a 30-s period after intraocular administration of a drop of 1% NH₄OH (c).

Figure 5

Effects of pretreatment with CPZ (40 mg kg⁻¹, i.p.) or vehicle on the following responses: the body temperature response to LPS (10 μg kg⁻¹, i.v.) or saline (a) and CAP (1 mg kg⁻¹, i.p.)-induced hypothermia (b). CPZ was administered 90 min before LPS or CAP.