On Fever Mechanisms & Preoptic Signalling
Sammanfattning: Fever, a 1-4 °C elevation of the body temperature, is part of the systemic inflammatory response to infection or tissue damage, and it is believed to be a potent host defence. The underlying physiological mechanisms of the febrile response are one of the two main objectives in this thesis, where studies conducted in whole animals (rats and mice), chiefly aimed at clarifying the cytokine cascade in fever. The other principal objective of this thesis was to gain a general understanding on the signalling properties of neurons in the thermoregulatory region of the brain, the preoptic area, through electrophysiological investigations in vitro of ion channels and impulse firing behaviour of medial preoptic neurons of rat. From these studies it was concluded that:The endogenous pyrogen tumour necrosis factor _ (TNF_) injected intraperitoneally causes fever independent of interleukin-1_ (IL-1_), but dependent on interleukin-6 (IL-6) in the central nervous system. The TNF__induced fever is triggered through release endoperoxides, since pre-administration of the cyclooxygenase inhibitor indomethacin, efficiently blocks the increased body temperature.An intraperitoneal injection of lipopolysaccharide (LPS) induces fever that is independent on central IL-1 binding to its receptors, since occupancy of central IL-1 receptors of the IL-1 receptor antagonist (IL-1ra), is unable to block the febrile response.The temperature in the central nervous system and in the peritoneum are similar during the febrile response with respect to onset, temporal characteristics and fever amplitude.The neurons of the medial preoptic nucleus respond to glutamate application with currents that can be attributed to ion channels of the AMPA-receptor type as well as of the NMDA-receptor type. The functional characteristics of these channels comprise fast activation and desensitization of the AMPA-receptor channel, as well as glycine dependency, Mg2+dependent outward rectification and slow desensitization kinetics of the NMDA-receptor channel.The medial preoptic neurons display two types of Ca2+ spikes, that result in two types of firing behaviour. First, low-threshold spikes depend on T-type Ca2+ channels and are generated from membrane potentials < -75 mV. They may induce short bursts of fast Na+ spikes. Second, high-threshold spikes can be generated from more depolarized levels, and depend on Ca2+channels that are mainly of the L, N and P -types. One role of these channels is to sustain long-burst firing.Medial preoptic neurons spontaneously fire with several types of temporal firing patterns. Apart from burst firing, neurons are silent or discharge regularly as well as irregularly. The type of firing pattern can be manipulated with steady current injection and possibly also by PGE2.
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