Department of Dental Anesthesiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
J Anesth. 2018 Oct;32(5):731-739. doi: 10.1007/s00540-018-2548-y. Epub 2018 Aug 30.
Neuronal inflammation is caused by systemic inflammation and induces cognitive dysfunction. IL-6 plays a crucial role in therapies for neuronal inflammation and cognitive dysfunction. Remifentanil, an ultra-short-acting opioid, controls inflammatory reactions in the periphery, but not in the brain. Therefore, the anti-inflammatory effects of remifentanil in neuronal tissue and the involvement of cAMP in these effects were investigated in the present study.
Mice were divided into 4 groups: control, remifentanil, LPS, and LPS + remifentanil. Brain levels of pro-inflammatory cytokine mRNA, and serum levels of corticosterone, catecholamine and IL-6 were measured in the 4 groups. The co-localization of IL-6 and astrocytes in the mouse brain after the LPS injection was validated by immunostaining. LPS and/or remifentanil-induced changes in intracellular cAMP levels in cultured glial cells were measured, and the effects of cAMP on LPS-induced IL-6 mRNA expression levels were evaluated.
Remifentanil suppressed increase in IL-6 mRNA levels in the mouse brain, and also inhibited the responses of plasma IL-6, corticosterone, and noradrenaline in an inflammatory state. In the hypothalamus, IL-6 was localized in the median eminence, at which GFAP immunoreactivity was specifically detected. In cultured cells, remifentanil suppressed increase in IL-6 mRNA levels and intracellular cAMP levels after the administration of LPS, and this enhanced IL-6 mRNA expression in response to LPS.
Remifentanil suppressed increase in IL-6 mRNA levels in the brain in an inflammatory state, and this effect may be attributed to its direct action on neuronal cells through the inhibition of intracellular cAMP rather than corticosterone.
神经元炎症是由全身炎症引起的，并导致认知功能障碍。白细胞介素-6（IL-6）在神经元炎症和认知功能障碍的治疗中起着至关重要的作用。瑞芬太尼是一种超短效阿片类药物，可控制外周的炎症反应，但不能控制大脑中的炎症反应。因此，本研究旨在探讨瑞芬太尼在神经元组织中的抗炎作用及其与 cAMP 的关系。
将小鼠分为 4 组：对照组、瑞芬太尼组、脂多糖（LPS）组和 LPS+瑞芬太尼组。测量 4 组小鼠脑内促炎细胞因子 mRNA 水平以及血清皮质酮、儿茶酚胺和 IL-6 水平。通过免疫染色验证 LPS 注射后小鼠脑中 IL-6 与星形胶质细胞的共定位。测量 LPS 和/或瑞芬太尼诱导的培养神经胶质细胞内 cAMP 水平的变化，并评估 cAMP 对 LPS 诱导的 IL-6 mRNA 表达水平的影响。
瑞芬太尼抑制了 LPS 诱导的小鼠脑内 IL-6 mRNA 水平的升高，并抑制了炎症状态下血浆中 IL-6、皮质酮和去甲肾上腺素的反应。在下丘脑中，IL-6 定位于正中隆起，其中特异性检测到 GFAP 免疫反应性。在培养的细胞中，瑞芬太尼抑制 LPS 给药后 IL-6 mRNA 水平和细胞内 cAMP 水平的升高，并增强了对 LPS 的 IL-6 mRNA 表达。
瑞芬太尼在炎症状态下抑制脑内 IL-6 mRNA 水平的升高，这种作用可能归因于其通过抑制细胞内 cAMP 而不是皮质酮对神经元细胞的直接作用。
