Targeting enkephalins and pituitary adenylate cyclase-activating polypeptide (PACAP) in migraine.
Targeting enkephalins and pituitary adenylate cyclase-activating polypeptide (PACAP) in migraine.
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DOI：
10.1093/brain/awac260
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发表时间：
2022-08-27
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偏头痛是一种普遍存在的神经系统疾病，影响着全世界超过10亿人。1其神经生物学基础涉及原发传入事件的激活，原发传入事件的细胞体位于三叉神经节和颈上神经节。主要传入事件被激活和致敏的机制尚不完全清楚，但有充分的证据支持特定肽在调节头痛的伤害性传递中的作用。事实上，一些针对降钙素基因相关肽（CGRP）或其受体的药物最近被证明对偏头痛有效。然而，相当一部分偏头痛患者对这些新药没有反应。因此，对额外药物发现的需求是明确的，今年发表在《大脑》杂志上的两项重要动物研究揭示了靶向脑啡肽和垂体腺苷酸环化酶激活多肽（PACAP）的治疗前景。1979年，Sicuteri第一个提出了偏头痛中阿片系统功能障碍的假说。2 β-内啡肽是一种内源性阿片神经肽。早期研究报道β-内啡肽水平的降低与脑脊液疾病的严重程度相关。据报道，偏头痛发作时血浆和血小板蛋氨酸-脑啡肽（MET）水平升高。在这一期的《大脑》杂志上，Descheemaeker等人报道了一项动物研究的结果，他们假设保护脑啡肽不受其降解酶的影响可能是偏头痛的一个可能的药物靶点。他们用动物模型来研究双脑啡肽酶抑制剂（DENKI） PL37对皮肤机械性异痛症的镇痛作用。PL37是一种抑制金属蛋白酶的小分子，从而保护脑啡肽免受其快速降解。反复给予一氧化氮供体硝酸异山梨酯（ISDN）诱导皮肤机械性异痛和三叉神经颈复合体（TCC）致敏。异位性痛觉被用来代替头痛。主要发现是单次口服PL37抑制isdn诱导的急性头性机械异位痛，单次静脉注射PL37抑制慢性头性机械异位痛，而非口服PL37。此外，每日口服PL37可预防头侧机械性异常痛，降低TCC中触摸诱导的c-Fos表达。在解释这些数据时，出现了两个问题：(i) DENKIs或delta-阿片受体激动剂是否具有滥用的可能性或在人类中引起安全性和耐受性问题；（ii）使用NO供体诱导机械性异常痛觉作为头痛替代的临床前模型是否对药物测试有用。前者尚未完全澄清，在治疗使用前应进行1期研究。为了进一步研究内源性阿片类药物在偏头痛中的作用，需要更多的研究使用脑脊液和血液生物标志物的验证分析。在这种情况下，内源性阿片类药物对治疗的反应可能发生的变化将引起人们的兴趣。关于第二个问题，重要的是要解决使用动物NO模型作为人类头痛或偏头痛的替代模型的概念。在人类中，NO模型已被用来测试抗偏头痛药物的功效。这些研究表明心得安、唑米曲坦和olcegepant（一种小分子CGRP受体拮抗剂）不能预防no诱导的头痛和偏头痛。此外，舒马曲坦不能减轻健康志愿者口服NO供体异山梨酯-5-单硝酸酯（5-ISMN）引起的头痛。…
Migraine is a ubiquitous neurological disease that affects more than one billion people worldwide. 1 Its neurobiological underpinnings involve activation of primary afferents whose cell bodies are located in the trigeminal ganglia and upper cervical ganglia. 1 The mechanisms by which the primary afferents become activated and sensitized remain incompletely understood, but there is ample evidence to support the role of specific peptides in modulating nociceptive transmission of cephalic pain. 1 Indeed, several drugs targeting calcitonin gene-related peptide (CGRP) or its receptor have recently proven efficacious for migraine. 1 However, a considerable proportion of people with migraine do not respond to these new medications. 1 The need for additional drug discovery is thus clear, and two important animal studies that were published in Brain this year shed light on the therapeutic promise of targeting enkephalins and pituitary adenylate cyclase-activating polypeptide (PACAP). In 1979, Sicuteri was the first to hypothesize dysfunction of the opioid system in migraine. 2 β-Endorphin is an endogenous opioid neuropeptide. Early studies reported that decreased levels of β-endorphin correlated with the severity of the disease in the CSF. 3 Elevated levels of plasma and platelets methionine-enkephalin (MET) were reported during migraine attacks. 4 In this issue of Brain, Descheemaeker et al. 5 report the results of an animal study in which they hypothesized that protecting enkephalins from their degrading enzymes could be a possible drug target for migraine. They used an animal model to investigate the analgesic effect of the Dual ENKephalinase Inhibitor (DENKI) PL37 on cutaneous mechanical allodynia. PL37 is a small molecule that inhibits metalloproteases and thereby protects enkephalins from their rapid degradation. Recurrent administration of the NO donor, isosorbide dinitrate (ISDN), was used to induce cutaneous mechanical allodynia and sensitization of the trigeminocervical complex (TCC). The allodynia was used as a surrogate for headache. The major finding was that single oral PL37 inhibited ISDN-induced acute cephalic mechanical allodynia and single intravenous, but not oral, PL37 administration inhibited chronic cephalic mechanical allodynia. In addition, daily oral administration of PL37 prevented cephalic mechanical allodynia and decreased touch-induced c-Fos expression in TCC. In interpreting these data, two questions arise:(i) whether DENKIs or delta-opioid receptor agonists would possess a potential for abuse or cause safety and tolerability issues in humans; and (ii) whether preclinical models using NO donors to induce mechanical allodynia as a surrogate for headache are useful for drug testing. The former is not completely clarified and should be investigated in phase 1 studies before therapeutic use. To further address the role of endogenous opioids in migraine, more studies using validated assays on CSF and blood-based biomarkers are needed. Possible changes in endogenous opioids in response to treatment will be of interest in this context. With regard to the second question, it is important to address the concept of using the NO model in animals as a surrogate model for headache or migraine in humans. In humans, NO models have been used to test the efficacy of anti-migraine drugs. These studies showed that propranolol, zolmitriptan and olcegepant (a small molecule CGRP receptor antagonist) failed to prevent NO-induced headache and migraine. In addition, sumatriptan failed to reduce headache induced by orally administered NO donor isosorbide-5-mononitrate (5-ISMN) in healthy volunteers. The …
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影响因子：
3.4
作者：
SICUTERI, F;DELBIANCO, PL;ANSELMI, B
通讯作者：
ANSELMI, B
影响因子：
4.9
作者：
Kokoti, Lili;Al-Karagholi, Mohammad Al-Mahdi;Ashina, Messoud
通讯作者：
Ashina, Messoud
影响因子：
7.4
作者：
GENAZZANI, AR;NAPPI, G;SAVOLDI, F
通讯作者：
SAVOLDI, F
影响因子：
14.5
作者：
Ernstsen, Charlotte;Christensen, Sarah L.;Kristensen, David M.
通讯作者：
Kristensen, David M.
DOI：
10.1177/0333102420970889
发表时间：
2021-01
期刊：
Cephalalgia : an international journal of headache
影响因子：
--
作者：
Ashina M;Doležil D;Bonner JH;Zhou L;Klatt J;Picard H;Mikol DD
通讯作者：
Mikol DD