Shiers Stephanie, Elahi Hajira, Hennen Stephanie, Price Theodore J
The University of Texas at Dallas, Center for Advanced Pain Studies and Department of Neuroscience, Richardson, TX, USA.
Grünenthal GmbH, Aachen, Germany.
Neurobiol Pain. 2021 Dec 21;11:100081. doi: 10.1016/j.ynpai.2021.100081. eCollection 2022 Jan-Jul.
The anterior cingulate cortex (ACC) is a critical region of the brain for the emotional and affective components of pain in rodents and humans. Hyperactivity in this region has been observed in neuropathic pain states in both patients and animal models and ablation of this region from cingulotomy, or inhibition with genetics or pharmacology can diminish pain and anxiety. Two adenylyl cyclases (AC), AC1 and AC8 play an important role in regulating nociception and anxiety-like behaviors through an action in the ACC, as genetic and pharmacological targeting of these enzymes reduces mechanical hypersensitivity and anxiety-like behavior, respectively. However, the distribution of these ACs in the ACC has not been studied in the context of neuropathic pain. To address this gap in knowledge, we conducted RNAscope hybridization to assess AC1 and AC8 mRNA distribution in mice with spared nerve injury (SNI). Given the key role of AC1 in nociception in neuropathic, inflammatory and visceral pain animal models, we hypothesized that AC1 would be upregulated in the ACC of mice following nerve injury. This hypothesis was also founded on data showing increased AC1 expression in the ACC of mice with zymosan-induced visceral inflammation. We found that AC1 and AC8 are widely expressed in many regions of the mouse brain including the hippocampus, ACC, medial prefrontal cortex and midbrain regions, but AC1 is more highly expressed. Contrary to our hypothesis, SNI causes an increase in AC8 mRNA expression in NMDAR-2B (Nr2b) positive neurons in the contralateral ACC but does not affect AC1 mRNA expression. Our findings show that changes in mRNA expression in the ACC are insufficient to explain the important role of this AC in mechanical hypersensitivity in mice following nerve injury and suggest a potential unappreciated role of AC8 in regulation of ACC synaptic changes after nerve injury.
前扣带回皮质（ACC）是啮齿动物和人类大脑中对疼痛的情绪和情感成分起关键作用的区域。在患者和动物模型的神经性疼痛状态下，该区域均出现了活动亢进的情况，而扣带回切开术对该区域的切除，或通过遗传学或药理学方法对其进行抑制，均可减轻疼痛和焦虑。两种腺苷酸环化酶（AC），即AC1和AC8，通过在ACC中的作用，在调节伤害感受和焦虑样行为方面发挥重要作用，因为对这些酶进行遗传学和药理学靶向分别可降低机械性超敏反应和焦虑样行为。然而，尚未在神经性疼痛的背景下研究这些AC在ACC中的分布情况。为了填补这一知识空白，我们进行了RNAscope杂交，以评估 spared nerve injury（SNI）小鼠中AC1和AC8 mRNA的分布。鉴于AC1在神经性、炎症性和内脏性疼痛动物模型的伤害感受中起关键作用，我们假设在神经损伤后的小鼠ACC中，AC1会被上调。这一假设还基于以下数据：在酵母聚糖诱导的内脏炎症小鼠的ACC中，AC1表达增加。我们发现AC1和AC8在小鼠大脑的许多区域广泛表达，包括海马体、ACC、内侧前额叶皮质和中脑区域，但AC1的表达更高。与我们的假设相反，SNI导致对侧ACC中NMDAR-2B（Nr2b）阳性神经元中AC8 mRNA表达增加，但不影响AC1 mRNA表达。我们的研究结果表明，ACC中mRNA表达的变化不足以解释该AC在神经损伤后小鼠机械性超敏反应中的重要作用，并提示AC8在神经损伤后ACC突触变化调节中可能存在未被认识的作用。
