The role of neuronal nitric oxide on current vocalization thresholds

神经元型一氧化氮合酶（NOS 1）是一种主要在脑和脊髓中表达的NOS的组成型亚型。一氧化氮合酶1（NOS 1）的终产物一氧化氮（NO）是伤害性信息传递途径中的重要信使，在伤害性感受中起重要作用。在大鼠中，将辣椒素注射到动物爪子后，NOS 1在脊髓中上调。NOS 1抑制剂可阻断大鼠对有害化学刺激的反应性增强。在野生型小鼠中，NOS 1基因缺陷的小鼠具有减少的晚期角叉菜胶诱导的热痛觉过敏和NOS 1抑制剂抑制炎症诱导的痛觉过敏。此外，在糖尿病大鼠与糖尿病诱导的痛觉过敏，NOS 1的表达减少相比，控制。因此，有证据表明NOS 1在伤害感受中起重要作用。然而，NOS 1在疼痛传递中的作用尚未完全了解，它可能会根据产生疼痛的损伤类型而变化。我们正在研究野生型和NOS 1基因缺陷小鼠，并使用一种非损伤性和神经特异性的方法来测量当前的发声阈值，这是疼痛耐受阈值的替代措施。我们将发声定义为本研究的疼痛回避行为终点，并测量了不同频率电刺激下的当前发声阈值。为了研究NOS 1在通过特定神经纤维传递伤害性刺激中的作用，我们以不同频率，5-Hz，250-Hz和2000-Hz，分别特异性刺激C，A δ和A β纤维，以增加的强度向皮肤（尾部）递送电刺激。激发疼痛回避行为（此处定义为发声）的电刺激强度定义为每个频率的电流发声阈值。与野生型小鼠相比，NOS 1缺陷小鼠具有更高的发声阈值。因此，我们正在研究这些发现的机制，并探讨NO和/或NOS 1本身是否是目前发声阈值基线变化的原因。我们已经证明，外源性来源的NO是不足以降低发声阈值在NOS-1缺陷的小鼠和大脑中的炎症细胞因子的表达增加NOS-1缺陷的小鼠。

Neuronal nitric oxide synthase (NOS1) is a constitutive isoform of NOS predominantly expressed in the brain and spinal cord. The end-product of NOS1, nitric oxide (NO), has been shown to be an important messenger in nociceptive signal transduction pathways and to play an important role in nociception. In rats, NOS1 is upregulated in the spinal cord after the injection of capsaicin into the animals paw. The increased responses to noxious chemical stimulus to the paw of rats were blocked by inhibitors of NOS1. Mice genetically deficient in NOS1 have reduced late phase carrageenan-induced thermal hyperalgesia and NOS1 inhibitors inhibited inflammation-induced hyperalgesia in wild type mice. Also, in diabetic rats with diabetes-induced hyperalgesia, the expression of NOS1 is decreased compared to controls. Therefore, there is evidence to indicate that NOS1 plays an important role in nociception. However, the role of NOS1 in the transmission of pain is not entirely understood and it may vary according to the types of injury that produce pain. We are studying wild type and NOS1 genetically deficient mice and using a non injurious and neurospecific method to measure current vocalization threshold a surrogate measure of pain tolerance thresholds. We define vocalization as the pain avoiding behavior end point of this study and measured current vocalization threshold to electrical stimulus delivered at different frequencies. In order to study the role of NOS1 in the transmission of noxious stimulus via specific nerve fibers, we deliver electrical stimuli to the skin (tail) at increasing intensities at different frequencies, 5-Hz, 250-Hz and 2000-Hz that specifically stimulate C, A delta, and A beta fibers respectively. The intensity of the electrical stimulus that elicits pain avoiding behavior (here defined as vocalization) is defined as current vocalization threshold for each frequency. Mice deficient in NOS1 have higher vocalization thresholds compared with wild type mice. We are therefore investigating the mechanisms of such findings, and exploring whether NO and/or NOS1 itself are responsible for the changes in current vocalization thresholds found at baseline. We have demonstrated that exogenous sources of NO are not sufficient to reduce vocalization thresholds in NOS1-deficient mice and that the expression of inflammatory cytokines in the brain is increased in NOS-1 deficient mice.