脂肪酸酰胺水解酶（FAAH）抑制剂 PF-3845 在神经系统中发挥作用，可逆转 LPS 诱导的小鼠触觉异常性疼痛。
The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice.
机构信息
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
出版信息
Br J Pharmacol. 2012 Apr;165(8):2485-96. doi: 10.1111/j.1476-5381.2011.01445.x.
BACKGROUND AND PURPOSE
Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non-noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB1 and CB2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with Δ(9) -tetrahydrocannabinol (THC).
EXPERIMENTAL APPROACH
Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS-induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses.
KEY RESULTS
FAAH (-/-) mice or wild-type mice treated with FAAH inhibitors (URB597, OL-135 and PF-3845) displayed an anti-allodynic phenotype. Furthermore, i.p. PF-3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF-3845 produced a partial reduction in allodynia. However, the anti-allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti-allodynic effects of FAAH-compromised mice required activation of both CB1 and CB2 receptors, but other potential targets of FAA substrates (i.e. µ-opioid, TRPV1 and PPARα receptors) had no apparent role.
CONCLUSIONS AND IMPLICATIONS
AEA is the primary FAAH substrate reducing LPS-induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain.
LINKED ARTICLES
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
背景与目的
炎症痛是一个具有临床相关性的问题，常引起痛觉过敏，即非伤害性刺激被感知为疼痛。内源性大麻素（大麻素）系统是治疗炎症痛的一个潜在靶点，该系统由 CB1 和 CB2 大麻素受体和几种内源性配体组成，包括花生四烯酸酰胺（AEA）。抑制代谢酶脂肪酸酰胺水解酶（FAAH）可提高 AEA 水平并产生镇痛作用，而不会产生与 Δ(9)-四氢大麻酚（THC）相关的致幻副作用。
实验方法
通过足底注射 LPS 诱导痛觉过敏。互补的遗传和药理学方法用于确定阻断 FAAH 以逆转 LPS 诱导的痛觉过敏的策略。使用质谱分析定量内源性大麻素水平。
主要结果
FAAH（-/-）小鼠或用 FAAH 抑制剂（URB597、OL-135 和 PF-3845）治疗的野生型小鼠表现出抗痛觉过敏表型。此外，腹腔注射 PF-3845 增加了大脑和脊髓中的 AEA 水平。此外，足底注射 PF-3845 可部分减轻痛觉过敏。然而，在神经元特异性烯醇酶启动子下仅在神经系统中表达 FAAH 的小鼠中，抗痛觉过敏表型缺失，这表明神经元脂肪酸酰胺（FAAs）的参与。FAAH 受损小鼠的抗痛觉过敏作用需要激活 CB1 和 CB2 受体，但 FAA 底物的其他潜在靶点（即 µ-阿片受体、TRPV1 和 PPARα 受体）似乎没有明显作用。
结论和意义
AEA 是降低 LPS 诱导的触觉痛觉过敏的主要 FAAH 底物。阻断神经元 FAAH 通过激活两种大麻素受体逆转痛觉过敏，代表了治疗炎症痛的有希望的靶点。
相关文章
本文是关于大麻素在生物学和医学中的主题部分的一部分。要查看该部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2012.165.issue-8。要查看大麻素在生物学和医学中的第 I 部分，请访问 http://dx.doi.org/10.1111/bph.2011.163.issue-7。
Zotero 插件