Protective Effect Of Naloxone On Cerebral Tissue And Microcirculation Changes In Endotoxicemia

Objective Naloxone has protective effects on some abnormalities such as brain damage, microcirculation disorder, myocardial ischemia, respiratory dysfunction, damage of intestines mucous membrane and metabolic abnormity. The mechanism of these effects may relate to endorphin and inflammatory mediators. But the reports about naloxone on brain inflammatory mediators and mesenteric microcirculation are not available. Our study was designed to investigate the protective effect of naloxone on the rats with endotoxicemia, and explore the mechanism of this drug in three aspects: inflammatory mediators, brain tissue and mesenteric microcirculation in rats.Method: A rat model of endotoxicemia was established by injection of LPS with a dose of 5mg/kg into thigh vein. The 80 SD rats were randomly divided into four groups: Control group, Endotoxin group, Naloxone +Endotoxin group and Dexamethasone +Endotoxin group, each group included 20 rats which were subdivided into 4 temporal subgroups (1h, 2h, 4h, 6h respectively). The mesenteric microcirculation of rats, white blood cell and arterial gas analysis, concentration of TNF-α, IL-1β, IL-6 in serum and brain homogenate were ivstigated. Furthermore, the brain tissue pathological changes were examined.Results: (1) In endotoxin group, the blood white cell of rats decreasedseverely, getting its bottom at 4h, and increased at 6h. PaO₂ dropped progressively and reached its bottom at 6h. Two hours after the injection of endotoxin, PH gained its minimum while PaCO₂ peaked. (2) In endotoxin group, serum TNF-α and IL-6 peaked at 2h, IL-1 peaked at 4h. Inflammatory mediators in brain homogenate did not parallel with those in serum. (3) Brain tissue pathological changes in endotoxin group were wide halo around neuron and micro vas, decreased size of neuron, red stained cytoplasm, lost Nissl body, cell nucleus rigidity, nucleolus disappear and matrix edema。 The changes got serious as time went by. (4) Endotoxin caused abnormal blood flow states, lower blood flow velocitya and fewer disparked capillary vessels, and leucocytes were stuck to vessel wall. In serious cases, blooding, embolism or even atrophy in micro vas were seen. (5) At the point of 2h, naloxone attenuate the changes of PaCO₂ and PH caused by endotoxin. It apparently increased PO₂ at 4h and decreased serum IL-1 , IL-6 at 1h and 2h. Rats of naloxone group had higher serum TNF-α than control group at lh, their brain tissue pathological changes were gentler at lh and 2h. (5) Dexamethasone decreased PaCO₂ at 2h and attenuate serum changes of serum TNF-α, IL-1, IL-6 and brain tissue pathology at 4h or so.Conclusion: 1. White blood cell decreased early after endotoxin, which tallied with our result in microcirculation such as leucocytes were stuck to vessel wall and wandering out. 2. In endotoxicemia, inflammatory mediators in serum don't parallel with those in brain, which indicates cortical inner mediators may contribute to the mechanism at some degree. 3. Naloxone can affect serum and cortical inflammatory mediators, which indicates that it has protective effect on endotoxicemia .This kind of effect emerges at lh and 2h after endotoxin and parallel with the pharmacokinetics character of naloxone. 4.