New pieces for the substance P puzzle.
New pieces for the substance P puzzle.
复制标题
P 物质拼图的新碎片。
DOI：
10.1016/j.pain.2013.04.020
复制
发表时间：
2013
期刊：
影响因子：
7.4
通讯作者：
Linnman,Clas
中科院分区：
文献类型：
--
作者：
Linnman,Clas
1931年，冯·欧拉和加达姆在马肠和脑的制备中发现了一种抗氧化活性物质，后来被称为P物质（SP;粉末）[26]。SP的分离被证明是困难的，直到40年后，在1971年，在牛下丘脑提取物中偶然发现促涎因子后才完成[20，23]。SP存在于感觉C纤维神经元中，并且在伤害性传入刺激后，SP在脊髓中释放。自然，SP长期以来被认为是一种“疼痛神经肽”。又过了20年，SP优选受体神经激肽-1受体（NK-1 R）才被鉴定和克隆[22]，并且第一种非肽NK-1 R拮抗剂药物被公开。自1991年以来，已经开发了几种结构多样化和高选择性的NK-1 R拮抗剂用于临床试验。此外，这些拮抗剂中的一些已被开发成正电子发射断层扫描（PET）配体，其主要用于确定药物受体占有率，这是临床试验中剂量选择的基本指南[4，5]。尽管临床前结果令人鼓舞，但临床研究并未发现对各种慢性疼痛状态的疗效，包括疼痛性糖尿病神经病变、疱疹后神经痛、偏头痛（急性和预防性）、内脏痛、骨关节炎和纤维肌痛[6，11]。通过PET证实了候选药物的脑渗透和靶点结合，排除了NK-1 R拮抗剂在疼痛调节中缺乏临床疗效是由于受体阻断不足的可能性[7，10]。此外，阿瑞匹坦（一种NK-1 R拮抗剂）的药理学功能MRI显示，对疼痛网络连接或反应性无显著调节[24]。因此，大型制药公司基本上放弃了他们的P物质疼痛计划。迄今为止，阿瑞匹坦和前体药物福沙匹坦是唯一FDA批准的NK-1 R拮抗剂，适用于化疗诱导的恶心和呕吐以及术后恶心和呕吐。银线是NK-1 R药物开发的大量投资为我们提供了评估NK-1 R系统的宝贵工具。PET配体[18 F] SPA-RQ和[11 C] GR 205171具有高亲和力和与NK-1 R的缓慢解离，表明它们是用于评估受体水平的良好试剂[3]。在这一期的疼痛，Jarcho等人。[12]利用这一特性测量了两个临床人群中的NK-1 R水平：炎症性肠病（IBD）患者和肠易激综合征（IBS）患者。患者组（和健康对照组）得到了很好的表征，允许进行一些非常有趣的比较。作者发现，在这两种情况下，NK-1 R的可用性都降低了，在IBD患者中尤其明显，而且这种降低似乎集中在前扣带回和基底神经节。此外，NK-1 R的可用性与IBD患者的GI症状相关，与IBS患者的疾病持续时间和疼痛敏感性相关。因此，NK-1 R与疾病表现之间的关系可能在患者组之间存在差异。这些发现与我们对挥鞭样损伤相关疾病（WAD II级）患者的研究一致，其中患者也显示前扣带回中NK-1 R的可用性降低。[17]第10段。然而，在WAD中，腹内侧前额叶皮层的减少最为明显，减少的幅度与对运动的恐惧有关。因此，似乎多种形式的慢性疼痛可能导致皮质和皮质下区域的NK-1 R可用性降低。需要进一步的研究来证实NK-1 R水平与临床症状的关系。
In 1931, von Euler and Gaddum discovered a pharmacologically active substance in preparations of the horse gut and brain, later nicknamed Substance P (SP; for powder)[26]. Isolation of SP proved difficult and was not accomplished until 40 years later, in 1971, following a chance finding of a sialogogic factor in bovine hypothalamic extracts [20, 23]. SP is found in sensory C-fiber neurons, and following stimulation of nociceptive afferents, SP is released in the spinal cord. Naturally, SP has long been considered a ‘‘pain neuropeptide’’. It took another 20 years before the SP preferred receptor, Neurokinin-1 receptor (NK-1R) was identified and cloned [22] and the first non-peptide NK-1R antagonist drug was publically disclosed. Since 1991, several structurally diverse and highly selective NK-1R antagonists have been developed for clinical trials. In addition, some of these antagonists have been developed into Positron Emission Tomography (PET) ligands, which are primarily used to determine drug receptor occupancy, an essential guide for dose selection in clinical trials [4, 5]. Despite promising preclinical results, clinical studies did not find efficacy in a variety of chronic pain states, including painful diabetic neuropathy, post-herpetic neuralgia, migraine (acute and preventive), visceral pain, osteoarthritis, and fibromyalgia [6, 11]. Brain penetration and target engagement by candidate drugs were confirmed with PET, which ruled out the possibility that the lack of clinical efficacy of NK-1R antagonists in pain modulation was due to inadequate blocking of receptors [7, 10]. Moreover, pharmacological functional MRI of aprepitant, an NK-1R antagonist, demonstrated no significant modulation of pain network connectivity or reactivity [24]. Accordingly, major pharma largely abandoned their Substance P pain programs. To date, aprepitant and the prodrug fosaprepitant are the only FDA approved NK-1R antagonists and these are indicated for chemotherapy-induced nausea and vomiting and for postoperative nausea and vomiting. The silver lining is that the heavy investments in NK-1R drug development gave us valuable tools to evaluate the NK-1R system. The PET ligands [18F] SPA-RQ and [11C] GR205171 have high affinity and slow dissociation from the NK-1R, suggesting that they are good agents for assessment of receptor levels [3]. In this issue of PAIN, Jarcho et al.[12] used this property to measure NK-1R levels in two clinical populations: patients with inflammatory bowel disease (IBD) and patients with irritable bowel syndrome (IBS). The patient groups (and healthy controls) were well characterized, allowing for some very interesting comparisons. The authors found that NK-1R availability is decreased in both conditions, particularly pronounced in patients with IBD, and that the reductions appear concentrated in the anterior cingulate and the basal ganglia. Moreover, NK-1R availability correlated with GI symptoms in IBD patients, and with duration of illness and pain sensitivity in IBS patients. Thus, the relationship between NK-1R and the manifestation of illness may differ between patient groups. These findings are consistent with our studies on patients with whiplash associated disorder (WAD grade II), in which patients also displayed a reduction of NK-1R availability in the anterior cingulate.[17]. In WAD, the reductions were however most pronounced in the ventromedial prefrontal cortex, and the magnitude of reduction related to fear of movement. Thus, it appears that multiple forms of chronic pain may lead to reduced NK-1R availability in cortical and subcortical regions. Further studies are needed to confirm how NK-1R levels relate to clinical symptoms …