Basic and clinical studies on the mechanisms of "psychogenic fever"

“心因性发热”是最常见的心身疾病之一。然而，目前尚不清楚心理应激如何增加这些患者的核心体温（Tc）。因此，为了阐明心理应激诱导的体温过高的机制，进行了以下实验。(1)为了确定前列腺素E2（PGE 2）诱导发热的关键脑区，我比较了脂多糖（LPS）诱导的Fos免疫反应性（Fos-ir）阳性细胞表达之间的EP 3受体基因敲除（KO）小鼠和野生型（WT）小鼠。LPS（10 μg/kg，腹腔注射）仅使WT小鼠的Tc（1.0℃）升高，并在中间外侧细胞柱中诱导Fos免疫反应阳性细胞。Fos-ir阳性细胞主要分布于两种小鼠的腹内侧视前区（VMPO）和中缝苍白核（RPa）。(2)为了研究心理应激是否激活LPS诱导发热期间激活的脑核团，我观察了大鼠VMPO和RPa中Fos-ir的表达。笼交换应激使Tc（0.9℃）升高，并诱导RPa中Fos免疫阳性细胞，但VMPO中无Fos免疫阳性细胞。(3)为了评估细胞因子和PGE 2在“心因性发热”患者高热中的作用，我研究了阿司匹林对Tc的影响，并比较了治疗前后致热性细胞因子如IL-1、11-6和MIP-1α的血液水平。阿司匹林（660 mg，口服，一天两次）未能减弱体温过高。治疗前（37.6℃）和治疗后（36.8℃）的血液细胞因子水平无差异。值得注意的是，4周的帕罗西汀，一种选择性5-羟色胺（5-HT）再摄取抑制剂，显著改善了持续性高热。这些发现表明：（1）VMPO可能不参与PSH，（2）心理应激通过细胞因子或PGE 2非依赖性机制增加Tc，（3）中枢5-HT能功能减退可能是应激诱导的持续性高热的原因。

"Psychogenic fever" is one of the most common psychosomatic diseases. However, it is still unknown how psychological stress increases core body temperature (Tc) in these patients. Therefore, to elucidate the mechanisms of psychological stress-induced hyperthermia, the following experiments were conducted.(1) To determine the brain regions crucial for prostaglandin E2 (PGE2)-induced fever, I compared lipopolysaccharide (LPS)-induced Fos-immunoreactivity (Fos-ir) positive cell expression between the EP3 receptor gene knockout (KO) mice and wild type (WT) mice. LPS (10 μg/kg, intraperitoneally) increased Tc (1.0℃) and induced Fos-ir positive cells in the intermediolateral cell column only in the WT mice. Fos-ir positive cells were observed in the ventromedial preoptic area (VMPO) and the raphe pallidus nucleus (RPa) in both mice.(2) To investigate if psychological stress activates brain nuclei that are activated during LPS-induced fever, I observed Fos-ir expression in the VMPO and the RPa in rats. Cage exchange stress increased Tc (0.9℃) and induced Fos-ir positive cells in the RPa but not in the VMPO.(3) To assess the involvement of cytokines and PGE2 in the hyperthermia of "psychogenic fever" patients, I investigated the effect of aspirin on Tc and compared blood levels of pyrogenic cytokines such as IL-1, 11-6, and MIP-1α between before and after treatment. Aspirin (660mg, p.o., twice a day) failed to attenuate the hyperthermia. Blood cytokine levels were not different between the pre (37.6℃) and post-treatment (36.8℃). To note, four weeks administration of paroxetine, a selective serotonin (5-HT) reuptake inhibitor, significantly improved persistent hyperthermia.These findings suggest that (1) the VMPO may not be involved in PSH, (2) psychological stress increases Tc via cytokines- or PGE2-independent mechanisms, and (3) central 5-HTergic hypofunction may account for stress-induced, persistent hyperthermia.