DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache.
DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache.
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DOI：
10.3389/fphar.2020.615028
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发表时间：
2020
影响因子：
5.6
通讯作者：
Largent-Milnes TM
中科院分区：
文献类型：
--
作者：
Levine A;Liktor-Busa E;Karlage KL;Giancotti L;Salvemini D;Vanderah TW;Largent-Milnes TM
最近的研究结果表明，临床内源性大麻素缺乏是包括偏头痛和头痛在内的疼痛障碍的病理生理基础。在由舒马曲坦或吗啡持续给药所致的药物滥用头痛模型中，中脑导水管周围灰质(PAG)中2-AG的水平选择性地被耗竭，而皮层中的ANA(AEA)水平则升高，提示头痛时内源性大麻素系统有明显的调节作用。这些结果导致了一种假说，即阻断DAGL，降低2-AG水平将导致头痛样行为，作为一种新的与翻译相关的阵发性头痛模型。我们的研究调查了非选择性和选择性阻断DAGL(2-AG的主要生物合成酶)是否会导致眶周和后爪痛觉过敏、畏光、焦虑样行为、对流产的抗偏头痛药物的反应性以及2-AG/AEA水平。注射非选择性DAGL(DH376，10 mg/kg，ip)和选择性DAGLα(LEI106，20 mg/kg，ip)抑制剂，但不注射DAGLβ制剂，雌雄大鼠的面部敏感率分别为100%和60%，而不诱发外周敏感性。值得注意的是，在DAGLα抑制后，雄性大鼠表现出明显低于雌性大鼠的敏感性，这表明在这一机制中存在性别二型性。重要的是，LEI106引起的眼眶周围疼痛可通过临床上可用的抗偏头痛药物舒马曲坦和奥昔洛韦来缓解。通过明-暗盒测量，选择性DAGLα抑制诱导了显著的畏光，没有焦虑样的行为或自主运动的变化。疼痛敏感度高峰时AEA和2-AG水平的分析显示，视觉皮质和中脑导水管周围灰质(PAG)中的2-AG水平降低，而ANANDAME和二酰甘油水平没有明显变化。这些结果为DAGL-2AG诱导头痛样疼痛和畏光而不伴有头外异位痛症提供了基础证据，从而模拟了临床发作性偏头痛。从机制上讲，DAGL抑制后头痛敏感性的行为学测量表明，驱动头痛开始的是皮质和PAG中2-AG信号的减少，而不是三叉神经尾侧核或三叉神经节。因此，发作性DAGL抑制可以减少目前公认的头痛模型的时间、成本和侵袭性，可能会满足对反映临床表现的发作性偏头痛/头痛模型的需求。此外，这种方法的使用可能为研究从阵发性头痛向慢性头痛的转变提供了一条途径。
Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the periaqueductal gray (PAG) and anandamide (AEA) increased in the cortex suggesting distinct regulation of the endocannabinoid system during headache pain. These results led to the hypothesis that blockade of DAGL, to reduce 2-AG levels would induce headache-like behaviors as a new, translationally relevant model of episodic headache. Our study investigated whether non-selective and selective blockade of DAGL, the main biosynthetic enzyme for 2-AG, induced periorbital and hind-paw allodynia, photophobia, anxiety-like behaviors, responsivity to abortive anti-migraine agents, and 2-AG/AEA levels. Injection of non-selective DAGL (DH376, 10 mg/kg, IP) and selective DAGLα (LEI106, 20 mg/kg, IP) inhibitors, but not DAGLβ agents, induced facial sensitivity in 100% and ∼60% of female and male rats, respectively, without induction of peripheral sensitivity. Notably, male rats showed significantly less sensitivity than female rats after DAGLα inhibition, suggesting sexual dimorphism in this mechanism. Importantly, LEI106 induced periorbital allodynia was attenuated by administration of the clinically available abortive antimigraine agents, sumatriptan and olcegepant. Selective DAGLα inhibition induced significant photophobia as measured by the light-dark box, without anxiety like behaviors or changes in voluntary movement. Analysis of AEA and 2-AG levels at the time of peak pain sensitivity revealed reductions in 2-AG in the visual cortex and periaqueductal gray (PAG), without altering anandamide or significantly increasing diacylglycerol levels. These results provide foundational evidence for DAGL-2AG in the induction of headache-like pain and photophobia without extracephalic allodynia, thus modeling the clinical episodic migraine. Mechanistically, behavioral measures of headache sensitivity after DAGL inhibition suggests that reduced 2-AG signaling in the cortex and PAG, but not the trigeminal nucleus caudalis or trigeminal ganglia, drives headache initiation. Therefore, episodic DAGL inhibition, which reduces the time, cost, and invasiveness of currently accepted models of headache, may fill the need for episodic migraine/headache models mirroring clinical presentation. Moreover, use of this approach may provide an avenue to study the transition from episodic to chronic headache.
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影响因子：
5.3
作者：
Akerman, Simon;Holland, Philip R.;Goadsby, Peter J.
通讯作者：
Goadsby, Peter J.
影响因子：
14.5
作者：
De Felice, Milena;Ossipov, Michael H.;Porreca, Frank
通讯作者：
Porreca, Frank
DOI：
10.1523/jneurosci.2671-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ho YC;Lee HJ;Tung LW;Liao YY;Fu SY;Teng SF;Liao HT;Mackie K;Chiou LC
通讯作者：
Chiou LC
影响因子：
4.9
作者：
Guy, N.;Marques, A. R.;Clavelou, P.
通讯作者：
Clavelou, P.
影响因子：
7.4
作者：
Andrews NA;Latrémolière A;Basbaum AI;Mogil JS;Porreca F;Rice ASC;Woolf CJ;Currie GL;Dworkin RH;Eisenach JC;Evans S;Gewandter JS;Gover TD;Handwerker H;Huang W;Iyengar S;Jensen MP;Kennedy JD;Lee N;Levine J;Lidster K;Machin I;McDermott MP;McMahon SB;Price TJ;Ross SE;Scherrer G;Seal RP;Sena ES;Silva E;Stone L;Svensson CI;Turk DC;Whiteside G
通讯作者：
Whiteside G