Fentanyl self-administration impacts brain immune responses in male Sprague-Dawley rats
Fentanyl self-administration impacts brain immune responses in male Sprague-Dawley rats
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DOI：
10.1016/j.bbi.2020.03.003
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发表时间：
2020-07-01
影响因子：
15.1
通讯作者：
Cisneros, Irma E.
中科院分区：
文献类型：
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作者：
Ezeomah, Chiomah;Cunningham, Kathryn A.;Cisneros, Irma E.
阿片类药物使用障碍（OUD）在美国影响着200多万人，是一个日益严重的公共卫生危机。芬太尼的滥用和强效芬太尼衍生物的出现增加了使用者死于过量的风险，也增加了发展OUD的风险。虽然目前人们的注意力集中在理解导致OUD的行为和神经功能的复杂性上，但关于阿片类药物摄入与中枢神经系统（CNS）免疫反应的相互作用仍有许多有待发现。在目前的研究中，我们测试了一个假设，即短期戒断芬太尼自我管理与先天免疫标志物的表达改变。训练雄性Sprague-Dawley大鼠自我给予芬太尼（0.0032 mg/kg/输注）至稳定，然后禁欲24小时。在参与OUD过程的神经回路的节点内，包括前额叶皮质（PFC）、中脑核（NAc）、尾壳核（CPu）、海马（HIP）和中脑（MB），询问了几种先天免疫标记物以及阿片受体（OR）和细胞内模式识别受体（PRR）。在本研究中，在芬太尼（相对于生理盐水）自我给药的短期戒断期间，PFC和MB中的免疫靶点很少受到影响。然而，细胞因子的表达增加[例如，白细胞介素（IL）1 β，IL 5]，趋化因子[例如，C-C基序趋化因子20（MIP 3 alpha）]、肿瘤坏死因子α（TNF alpha）和干扰素（IFN）蛋白（例如，在NAc中观察到IFN β和IFN γ）]，而细胞因子（例如，几种IL），趋化因子[例如，粒细胞-巨噬细胞集落刺激因子（GMCSF），单核细胞趋化蛋白（MCP）MCP 1，MIP 3 α]，趋化因子配体5（RANTES）和干扰素（例如，IFN β和IFN γ）。芬太尼累积摄入量与NAc中IL 1 β和IL 6的表达呈正相关，与HIP中IFN β、IL 2、IL 5、IL 12 p70和IL 17呈显著负相关。在芬太尼自我给药早期戒断期间，观察到OR表达的变化很少。令人兴奋的是，PRR，干扰素基因刺激因子（STING）的表达与累积芬太尼摄入量呈负相关，并与HIP中的特定细胞因子，趋化因子和干扰素蛋白显著相关。虽然CPu似乎相对不易受先天免疫标志物变化的影响，但在CPu中测量到累积芬太尼摄入量与MAVS和/或STING之间的最高相关性。我们的研究结果提供了中枢神经系统先天免疫反应的第一个证据，并暗示STING是芬太尼自我给药短期戒断期间免疫调节的新机制靶点。
Opioid use disorder (OUD) affects over two million in the United States and is an increasing public health crisis. The abuse of fentanyl and the emergence of potent fentanyl derivatives increases the risk for the user to succumb to overdose, but also to develop OUD. While intense attention is currently focused on understanding the complexity of behaviors and neural functions that contribute to OUD, much remains to be discovered concerning the interactions of opioid intake with the immune response in the central nervous system (CNS). In the present studies, we tested the hypothesis that short-term abstinence from fentanyl self-administration associates with altered expression of innate immune markers. Male Sprague-Dawley rats were trained to self-administer fentanyl (0.0032 mg/kg/infusion) to stability followed by 24 h of abstinence. Several innate immune markers, as well as opioid receptors (ORs) and intracellular pattern recognition receptors (PRRs), were interrogated within nodes of the neurocircuitry involved in OUD processes, including the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIP) and midbrain (MB). In the present study, few immune targets were impacted in the PFC and MB during short-term abstinence from fentanyl (relative to saline) self-administration. However, increased expression of cytokines [e.g., interleukin (IL)1 beta, IL5], chemokines [e.g., C-C motif chemokine 20 (MIP3 alpha)], tumor necrosis factor alpha (TNF alpha) and interferon (IFN) proteins (e.g., IFN beta and IFN gamma)] was seen in the NAc, while decreased expression of cytokines (e.g., several ILs), chemokines [e.g., granulocyte-macrophage colony-stimulating factor (GMCSF), monocyte chemoattractant protein (MCP) MCP1, MIP3 alpha ], the chemokine ligand 5 (RANTES) and interferons (e.g., IFN beta and IFN gamma) in the HIP. Positive correlations were observed between cumulative fentanyl intake and expression of IL1 beta and IL6 in the NAc, and significant negative correlations with fentanyl intake and IFN beta, IL2, IL5, IL12p70 and IL17 in the HIP. Few changes in OR expression was observed during early abstinence from fentanyl self-administration. Excitingly, the expression of the PRR, stimulator of interferon genes (STING) negatively correlated with cumulative fentanyl intake and significantly correlated to specific cytokines, chemokines and interferon proteins in the HIP. Although the CPu appears relatively invulnerable to changes in innate immune markers, the highest correlations between cumulative fentanyl intake with MAVS and/or STING was measured in the CPu. Our findings provide the first evidence of CNS innate immune responses and implicate STING as novel mechanistic targets of immunomodulation during short-term abstinence from fentanyl self-administration.