Lipopolysaccharide fever is initiatedviaa capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

Abstract

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.

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

“…This solution was injected (3.3 ml/kg) via the peritoneal catheter. The RTX dose (500 ng/kg) delivered was below the minimal dose known to cause long-term desensitization (Dogan et al, 2004) but was within the dose range known to cause shortterm hypothermia in mice . Control mice were injected with the vehicle (25% ethanol).…”

“…To cause localized (intra-abdominal) or systemic desensitization of TRPV1 channels, rats were injected with RTX intraperitoneally at a dose of 20 or 200 g/kg, respectively (Dogan et al, 2004). A working solution of RTX (20 or 180 g/ml) containing 20% ethanol was prepared.…”

“…After topical application of an irritant (e.g., a vanilloid compound) to the eye, a rat instinctively wipes the stimulated eye with the ipsilateral front paw, a response known to involve the TRPV1 channel (Dogan et al, 2004;Gavva et al, 2005b). To test whether TRPV1 channels in the cornea are desensitized, a drop (20 l) of a solution of RTX (2 g/ml) in 10% ethanol was applied to the cornea, and eye-wiping movements were counted for 5 min.…”

“…Many TRPV1-containing afferents travel within the spinal nerves and the vagus and innervate the abdominal viscera Hwang et al, 2005;Bielefeldt et al, 2006). To test the hypothesis that AMG0347 causes hyperthermia by acting on intra-abdominal targets, we induced localized desensitization of TRPV1 channels in the abdominal viscera, as in the past (Dogan et al, 2004). This method is based on the well established fact that a single dose of a TRPV1 agonist (e.g., capsaicin and RTX) can make the TRPV1 channel unresponsive to subsequent stimulation.…”

“…5) in this model of localized desensitization, as well as in rats with systemic desensitization of TRPV1 channels [caused by a high (200 g/kg, i.p.) dose of RTX (Dogan et al, 2004)] and in nondesensitized rats (treated with the vehicle). All tests were conducted 6 -13 d after the initial administration of RTX or its vehicle.…”