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A vasopressinergic pathway within the brain and its role in drug-induced antipyresis and pyrogenic tolerance

University of British Columbia

There is strong evidence which supports a physiological role for arginine vasopressin (AVP) in the negative modulation of the febrile process within the central nervous system (CNS). This evidence arises from a variety of experimental techniques employed in a number of different animal models. The CNS locus of action for AVP-mediated antipyresis is within a rostral diencephalic site called the ventral septal area (VSA). It has become evident that the mechanism by which AVP and aspirin-like drugs transduce changes in febrile body temperature are similar. Moreover, antipyretic drugs and AVP may share a common CNS locus of action. Therefore, investigations were conducted to determine whether antipyretic drugs are functionally linked to the endogenous antipyretic system of the brain. In addition, an examination of the role for centrally acting AVP and the natural suppression of fever during pyrogenic tolerance to endotoxin was conducted. AVP receptor antagonists of the peripheral V₁ and V₂ sub-type or saline control were microinjected into the VSA of rats rendered febrile by an intracerebroventricular (icv) injection of E. coli endotoxin, to assess the effects on the antipyresis elicited by indomethacin. Blockade of central V₁ but not V₂ receptors significantly attenuated the antipyretic effects of indomethacin given intraperitoneally. This effect was even more pronounced when the V₁ antagonist was infused for 30 min before and for 60 min after indomethacin administration. The V₁ analogue alone was without thermoregulatory effects. In order to determine whether the above effects were applicable to antipyretic drugs in general, central V₁ blockade was performed in the febrile rat subsequently treated with intraperitoneal sodium salicylate or acetaminophen. Salicylate-induced antipyresis was blocked, in a dose related manner, by VSA administration of the AVP V₁ antagonist. The fever reducing capacity of acetaminophen was unaffected by central V₁ blockade. Collectively these antipyretic drug studies, suggest that some but not all antipyretic drugs activate the endogenous AVP antipyretic pathway within the brain. Moreover, these data suggest that the mechanism of action of antipyretic drugs can no longer be simply explained as an action on prostaglandin biosynthesis. Endogenous release of AVP from VSA nerve terminals during endotoxin fever and drug-induced antipyresis was examined using the technique of push-pull perfusion. The release of AVP into the perfusion fluid remained unaltered by indomethacin injected into the non-febrile rat. However, during fever indomethacin prompted both an antipyresis as well as a significant increase in AVP release. Acetaminophen injected intraperitoneally also evoked an antipyresis but with no concomitant release of AVP within the VSA. These results are consistent with the antagonist studies. The effects on central AVP release by indomethacin appear to be related to the pyrogen employed because the drug did not evoke the release of AVP when administered prior to the hyperthermia produced by icv PGE₂. Indeed, PGE₂ itself stimulated AVP release which was inhibited by indomethacin treatment. These results are not consistent with an antipyretic role for AVP and await further clarification. Analysis of the release of AVP into the plasma and cerebrospinal fluid (CSF) were conducted during the fever evoked by intravenous endotoxin and subsequent to antipyretic intervention. Intravenous endotoxin was a provocative stimulus for plasma AVP release. Endotoxin-stimulated plasma AVP levels were unaffected by intraperitoneal injections of indomethacin, sodium salicylate or acetaminophen. In non-febrile controls, indomethacin, and to some extent acetaminophen, prompted increases in plasma AVP; although the temporal course of this release was different between the two drugs. Within the CSF, endotoxin treatment did not alter the normal diurnal rhythm of AVP release. Indomethacin treatment significantly suppressed CSF AVP release in non-febrile animals. A similar but non-significant trend was observed in febrile rats. Collectively, these studies demonstrate the independent regulation of AVP release within three separate biological compartments in response to febrogenic and antipyretic stimuli. The suppression of fever after repeated daily intravenous injections of bacterial endotoxins was thought to be exclusively a hepatic phenomenon. Experiments were conducted to determine whether a central mechanism involving AVP may also contribute to the antipyretic state observed during pyrogenic tolerance. In endotoxin tolerant animals, administration of a V₁ but not V₂ AVP receptor antagonist within the VSA, resulted in a significant reversal of the tolerant pyrogenic response. These data support the hypothesis that the central endogenous antipyretic system, involving AVP, plays a role in the mechanism of endotoxin tolerance. Tolerance does not develop following repeated central injections of pyrogens. Further experiments were performed to determine whether tolerance-induced activation of the antipyretic pathway would render an animal hyporesponsive to centrally administered pyrogens. When injected icv, during active endotoxin tolerance, the thermoregulatory responses to PGE₂ or endotoxin were not significantly suppressed from non-tolerant controls. However, analysis of VSA push-pull perfusates performed during a tolerant reaction to intravenous endotoxin revealed that increased AVP activity occurs within the first 30 min after the intravenous injection, well before the time PGE₂ or endotoxin were injected into the cerebral ventricles. This suggests that the antipyretic system is only activated briefly and may explain why centrally evoked fevers were unaffected during active endotoxin tolerance. In summary, this thesis research has demonstrated a direct functional link between the mechanism of action of antipyretic drugs and the endogenous antipyretic system within the brain. These results call into question the hypothesis whereby the fever reducing properties of antipyretic drugs can be explained exclusively as a result of the inhibition of prostaglandin biosynthesis. In addition, the differential effects on AVP release by antipyretic drugs suggests a number of biological pathways that can be activated by these drugs. Finally, a role for the AVP endogenous antiypretic system in the suppression of fever during endotoxin tolerance was established.

Text

2011-02-17

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http://hdl.handle.net/2429/31414

Physiology

University of British Columbia

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