Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
Department of Anatomy, Research Group for Mood Disorders, Centre for Neuroscience, Medical School and Szentagothai Research Centre, University of Pécs, Pécs, Hungary.
Am J Physiol Endocrinol Metab. 2022 Jan 1;322(1):E10-E23. doi: 10.1152/ajpendo.00223.2021. Epub 2021 Nov 15.
Cholecystokinin (CCK) increases core body temperature via CCK receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response. An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.
胆囊收缩素 (CCK) 通过中枢内注射 (icv) 时的 CCK 受体增加核心体温。CCK 引起的发热机制尚不清楚，也不知道 CCK 是否有助于对全身炎症的发热反应。我们研究了中枢 CCK 信号与环氧化酶 (COX) 途径之间的相互作用。成年雄性 Wistar 大鼠经腹腔内输注非选择性 COX 酶抑制剂甲灭酸（120mg/kg）或选择性 COX-2 抑制剂美洛昔康或依托考昔（两者均为 10mg/kg）预处理后，测量体温，30 分钟后给予中枢内 CCK（1.7μg/kg）。在单独的实验中，通过 c-Fos 免疫组织化学研究了与体温调节和摄食相关核中 CCK 诱导的神经元激活（有无 COX 抑制）。CCK 在输注后 10 分钟使体温升高约 0.4°C，甲灭酸可减弱该作用。CCK 减少了中前脑区（约 70%）的 c-Fos 阳性细胞数，但增加了下丘脑背侧区和中脑吻侧苍白球（两者均增加约 50%）；所有这些变化都被甲灭酸完全阻断。相比之下，CCK 诱导的饱食和腹内侧下丘脑的神经元激活不受甲灭酸影响。两种研究的选择性 COX-2 抑制剂也完全阻断了 CCK 诱导的发热。最后，CCK 受体拮抗剂 YM022（10μg/kg icv）减弱了细菌脂多糖（10μg/kg；静脉内）诱导的发热的后期阶段。我们得出结论，中枢内给予的 CCK 通过改变“经典”热敏效应途径的活性引起发热，而 COX-2 的激活是产生这种反应所必需的。已经提出了中枢胆囊收缩素信号与环氧化酶-前列腺素 E 途径之间的关联，但仍知之甚少。我们表明，中枢内给予胆囊收缩素引起的体温升高改变了传出热敏效应途径内的神经元活动，而这些作用被环氧化酶的抑制完全阻断。我们还表明，COX-2 的激活是 CCK 引起的发热效应所必需的，并且胆囊收缩素是内毒素诱导发热的调节剂。
