Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice
Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice
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DOI：
10.1523/eneuro.0106-22.2022
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发表时间：
2022-07-01
期刊：
影响因子：
3.4
通讯作者：
Vendruscolo, Leandro F.
中科院分区：
文献类型：
--
作者：
Alvarez-Bagnarol, Yocasta;Marchette, Renata C. N.;Vendruscolo, Leandro F.
阿片类药物的戒断涉及到动机和躯体症状的表现。然而，参与不同阿片类药物戒断迹象表达的大脑结构仍不清楚。我们通过反复注射剂量递增的海洛因在C57BU6J雄性和雌性小鼠中诱导阿片依赖。我们评估了海洛因自发戒断过程中的痛敏反应，以及首选的Mu阿片受体拮抗剂纳洛酮引起的躯体戒断迹象。海洛因处理的小鼠比生理盐水处理的小鼠表现出更高的痛觉过敏和躯体体征。在行为评估之后，我们通过自动计数c-Fos表达(细胞活动的标志)来测量大脑活动的区域变化。使用主成分分析，我们确定了行为(痛觉过敏和躯体戒断迹象)与不同脑区c-Fos表达之间的关联。痛觉过敏与c-Fos在下丘脑外侧核、杏仁中央核、腹侧被盖区、臂旁核、中缝背核和蓝斑的表达有关。躯体戒断与丘脑室旁核、外侧缰核、DR和LC的c-Fos表达有关。因此，痛觉过敏和躯体戒断症状都与c-Fos在特定脑区的表达有关。C-Fos在DR和LC中的表达与痛觉过敏和躯体戒断有关。了解急性和长期阿片类药物戒断的常见神经生物学机制可能有助于确定治疗阿片类药物使用障碍这一突出方面的新靶点。
Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BU6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential mu-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central nucleus of the amygdala, ventral tegmental area, parabrachial nucleus, dorsal raphe (DR), and locus coeruleus (LC). Somatic withdrawal was associated with c-Fos expression in the paraventricular nucleus of the thalamus, lateral habenula, DR, and LC. Thus, hyperalgesia and somatic withdrawal signs were each associated with c-Fos expression in unique sets of brain areas. The expression of c-Fos in the DR and LC was associated with both hyperalgesia and somatic withdrawal. Understanding common neurobiological mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of opioid use disorder.