Levine Aidan, Liktor-Busa Erika, Karlage Kelly L, Giancotti Luigi, Salvemini Daniela, Vanderah Todd W, Largent-Milnes Tally M
Department of Pharmacology, University of Arizona, Tucson, AZ, United States.
Department of Pharmacology and Physiology, Saint Louis University, St. Louis, MO, United States.
Front Pharmacol. 2021 Jan 12;11:615028. doi: 10.3389/fphar.2020.615028. eCollection 2020.
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.
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性疾病病理生理学的基础。在通过持续给予舒马曲坦或吗啡诱导的药物过量使用性头痛模型中，导水管周围灰质（PAG）中的2-花生四烯酸甘油（2-AG）水平选择性降低，而皮质中的花生四烯酸乙醇胺（AEA）增加，这表明在头痛疼痛期间内源性大麻素系统存在不同的调节机制。这些结果导致了这样一种假设，即阻断二酰甘油脂肪酶（DAGL）以降低2-AG水平会诱发类似头痛的行为，作为一种新的、与发作性头痛相关的转化模型。我们的研究调查了DAGL（2-AG的主要生物合成酶）的非选择性和选择性阻断是否会诱发眶周和后爪异常性疼痛、畏光、焦虑样行为、对中止偏头痛药物的反应性以及2-AG/AEA水平。注射非选择性DAGL（DH376，10mg/kg，腹腔注射）和选择性DAGLα（LEI106，20mg/kg，腹腔注射）抑制剂，但不注射DAGLβ制剂，分别在100%的雌性大鼠和~60%的雄性大鼠中诱发面部敏感性，而不会诱发外周敏感性。值得注意的是，DAGLα抑制后，雄性大鼠的敏感性明显低于雌性大鼠，这表明该机制存在性别差异。重要的是，临床上可用的中止偏头痛药物舒马曲坦和olcegepant可减轻LEI106诱导的眶周异常性疼痛。通过明暗箱测量发现，选择性DAGLα抑制可诱发明显的畏光，而不会出现焦虑样行为或自主运动的改变。在疼痛敏感性峰值时对AEA和2-AG水平的分析显示，视觉皮质和导水管周围灰质（PAG）中的2-AG减少，而花生四烯酸乙醇胺没有改变，二酰甘油水平也没有显著增加。这些结果为DAGL-2AG在诱发类似头痛的疼痛和畏光而无颅外异常性疼痛方面提供了基础证据，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测量表明，皮质和PAG中2-AG信号的减少，而不是三叉神经尾核或三叉神经节中的减少驱动了头痛的发作。因此，发作性DAGL抑制减少了目前公认的头痛模型的时间、成本和侵入性，可能满足对反映临床症状的发作性偏头痛/头痛模型的需求。此外，使用这种方法可能为研究从发作性头痛向慢性头痛的转变提供一条途径。
