Search

Direct administration of interleukin-1beta (IL-1beta) into the lateral cerebral ventricle of rat brain, in addition to inducing febrile responses, upregulated the immunoreactivity of tryptophan hydroxylase in the preoptic anterior hypothalamus. The fever induced by IL-1beta was significantly attenuated by pretreatment with intracerebroventricular injection of 5-HT2A receptor antagonists including cyproheptadine, ketanserin, or mianserin. In addition, the IL-1beta-induced fever was mimicked by intracerebroventricular administration of a 5-HT2A receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-amionpropane (DOI). The DOI-induced (present results) or IL-1beta-induced (previous results) fever was further attenuated by pretreatment with an intracerebroventricular dose of mu-opioid receptor antagonists (e.g., buprenorphine or cyclic d-phe-cys-Try-d-Arg-Thr-pen-Thr-NH2) or 5-HT receptor antagonists (e.g., ketanserin or cyproheptadine). These findings suggest that a 5-HT2A-mu opioid receptor mechanism in the hypothalamus may mediate the IL-1beta fever.

At first, we investigated whether both beta-endorphin release level in the hypothalamus and body temperature can be altered after intracerebroventricular (i.c.v.) injection of either lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), or prostaglandin E(2) (PGE(2)) in rats. It was found that in the rat, i.c.v. administration of either LPS (0.5 microg in 10 microl), IL-1beta (10 ng in 10 microl), or PGE(2) (200 ng in 10 microl), in addition to producing fever, upregulated the immunoreactivity of beta-endorphin in the preoptic anterior hypothalamus of rat brain. Secondarily, we assessed whether the fever induced by either LPS, IL-1beta, or PGE(2) can be altered by pretreatment with buprenorphine (an opioid receptor antagonist). The results revealed that i.c.v. administration of buprenorphine (1 - 10 microg in 10 microl) alone had an insignificant effect on the body temperature. However, the fever induced by i.c.v. injection of either LPS, IL-1beta, or PGE(2) was significantly attenuated by pretreatment with i.c.v. injection of buprenorphine 1 h before the pyrogen injection in rats. The results suggest that pyrogens enhance beta-endorphin release in the hypothalamus and trigger fever which can be attenuated by buprenorphine, an opioid receptor antagonist.

Whether the glutamate release in the organum vasculosum laminae terminalis (OVLT) is attributable to genesis of a pyrogenic fever is unclear. The lack of information led us to evaluate the changes in glutamate concentrations of OVLT during the fever induced by staphylococcal enterotoxin A (SEA) in unanesthetized rabbits. Both the OVLT concentrations of glutamate and the colonic temperatures were simultaneously monitored during systemic injection of SEA, MK801 (an N -methyl- d -aspartate (NMDA) receptor channel blocker), ketamine (an NMDA receptor channel blocker), or normal saline. The extracellular dialysates in the brain were collected using a microdialysis probe previously placed in the OVLT region. The concentrations of glutamate in the microdialysates were measured by a high-pressure liquid chromatography in combination with a fluorescence detector. Systemic administration of SEA (30 ng kg −1 I.V.) increased both the concentrations of glutamate in the OVLT and the colonic temperatures. Glutamate appeared to rise slightly earlier than body temperature. Pretreatment or posttreatment with MK801 or ketamine significantly attenuated the SEA-induced augmenting glutamate release in the OVLT and fever in rabbits. The suppression of glutamate release appeared to start slightly earlier than temperature decline. In addition, the SEA-induced fever could be mimicked by direct injection of glutamate or SEA into the OVLT area. The fever induced by intra-OVLT injection of SEA or glutamate was significantly attenuated by pretreatment with an intra-OVLT dose of MK801 (5 μg) or ketamine (10 μg). The results suggest that glutamatergic pathways in the OVLT region are in pyrogenic fever genesis.