Alteration of the physiological responses to indomethacin by endotoxin tolerance in the rat: a possible role for central vasopressin.

Abstract

1. Previous studies suggest that arginine vasopressin (AVP) is released into the ventral septal area (VSA) of the rat brain during the antipyresis induced by the cyclo-oxygenase inhibitor indomethacin. In addition, there is evidence for increased AVP transmission in the VSA of animals having a reduced pyretic response following three intravenous injections of bacterial endotoxin (LPS) (endotoxin tolerant). Since ventral septal AVP receptors can also become 'sensitized' following exposure to AVP, we questioned whether the antipyretic action of indomethacin would increase, via an action involving central AVP, if this drug were administered into LPS-tolerant rats.2. Intraperitoneal indomethacin (7'5 mg kg') was effectively antipyretic when administered 2 h after an intravenous challenge with LPS (50 ,ug kg') into conscious unrestrained rats. This dose of indomethacin had no effect on the core temperature of non-febrile rats given intravenous 0 9 % pyrogen-free saline. 3. Three intravenous injections of LPS over a period of 3 days resulted in rats that were tolerant to the pyrogenic effects of LPS. When indomethacin was administered 2 h following the third LPS injection, a dose-dependent hypothermia was observed. This effect was age dependent, as profound hypothermia was seen in 8 week but not 20 week old rats. 4. A mortality rate of 41% (P = 0 02) was observed within 24 h of indomethacin treatment in 8 week old tolerant rats compared with 0% in 8 week old non-tolerant and 20 week old tolerant rats. 5. The hypothermic and lethal effects of intraperitoneal indomethacin were not observed in young rats pretreated with bilateral microinjections of an AVP V1 receptor antagonist within the VSA, whereas hypothermia and lethal effects were seen in saline pretreated controls. 6. These results indicate that the physiological effects of indomethacin are dramatically altered in LPS-tolerant rats and that endogenous AVP may have a role in this process. The lack of indomethacin-induced deleterious effects in older rats indicates an age susceptibility to the antipyretic drug reminiscent of that seen in humans with Reye's syndrome.

Bacterial Lipopolysaccharide‐Induced Changes in FOS Protein Expression in the Rat Brain: Correlation with Thermoregulatory Changes and Plasma Corticosterone

“…The thermal responses to LPS administration are more commonly associated with fever (6,25), however, in the present study the direction of the change in body temperature induced by LPS was found to be dspendent on the dose of LPS administered. Previously observed hypothermic as well as febrile responses to LPS administration (6,26,27) may be explained by the observation that the occurrence of fever is dependent upon experimental conditions.…”

Tolerance to the anhedonic effects of lipopolysaccharide is associated with changes in syntaxin immunoreactivity in the nucleus accumbens

“…For instance, sub-chronic exposure to LPS leads to a rapid tolerance to the febrile (Wilkinson and Pittman, 1994 ;Zeisberger and Roth, 1998) and locomotor-depressing effects (Engeland et al, 2001). Tolerance to the anorectic effects of LPS was also demonstrated ; for example, Langhans et al (1991) noted that rats given a comparable dose of LPS to those in the present study exhibited an attenuated anorectic response by the third day of treatment, which is consistent with the duration required to exhibit tolerance to the anhedonic effects of the antigen on ICSS responding.…”

“…This may be essential for the survival of the animal, as a controlled inflammatory response is required to ensure that the organism is not overwhelmed by the detrimental physiological effects of prolonged immune activation (McEwen, 2000). Tolerance to repeated exposure to LPS has been demonstrated with regards to the febrile response (Almeida et al, 1999 ;Wilkinson and Pittman, 1994), locomotor depressing properties (Engeland et al, 2001) and anorectic effects (Langhans et al, 1991 ;Nava and Carta, 2000). However, it is unknown whether or not a tolerance develops to the anhedonic properties of LPS following repeated exposure.…”

Induction of arginine vasopressin-enhanced green fluorescent protein expression in the locus coeruleus following kainic acid-induced seizures in rats

“…The bad side is that AVP may exert a bad influence on the trigger of the seizure (Wilkinson and Pittman 1994). The good side is that AVP may work to modify the stress (Caldwell et al 2008), paralleling the synthesis of AVP in the parvocellular division of the PVN (Aguilera and Rabadan-Diehl 2000).…”