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A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase

机译：在缺乏脂肪酸酰胺水解酶的小鼠中揭示了伤害感受前的表型

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Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic deletion of FAAH may predispose animals to increased sensitivity to certain types of pain. More work is necessary to determine whether such changes could explain the lack of efficacy of FAAH inhibitors in clinical trials.
机译：脂肪酸酰胺水解酶（FAAH）是负责降解内源性大麻素anandamide的主要酶。在临床前的疼痛模型中，FAAH（FAAH KO）的药理抑制作用或基因缺失可产生抗伤害感受，这在很大程度上归因于由anandamide诱导的大麻素受体活化。但是，FAAH会代谢范围广泛的结构相关的，具有生物活性的脂类信号分子，其功能仍然未知。这些内源性脂质中的某些，包括anandamide本身，在某些条件下可能会产生伤害感受的作用。在我们的研究中，FAAH KO小鼠在甩尾试验以及炎性伤害感受的福尔马林和角叉菜胶模型中均表现出特征性的镇痛表型。尽管如此，相对于野生型小鼠，皮内注射瞬态受体电位通道V1（TRPV1）激动剂辣椒素增加了FAAH KO的伤害行为以及机械和热超敏反应。这种伤害感受型的表型伴随着辣椒素诱发的脊髓背角区域中的Fos样免疫反应（FLI）细胞的增加，涉及伤害感受过程，并被CB 1 （AM251）和TRPV1（AMG9810）减弱）拮抗剂。建立中枢敏化后，与野生型小鼠相比，FAAH KO小鼠的爪子皮肤和腰椎脊髓均显示出升高的anandamide，其他脂肪酸酰胺和内源性TRPV1激动剂水平。辣椒素降低了脊髓和爪皮肤中脊髓2-AG的含量，并增加了花生四烯酸和前列腺素E2的含量，而与基因型无关。我们的研究确定了辣椒素激发​​未掩盖的FAAH KO小鼠中以前无法识别的伤害感受表型。 CB 1 和TRPV1受体介导了较高的伤害感受反应，并伴随着增强的脊髓神经元活化。此外，FAAH的基因缺失对周围和中央脂质组有深远的影响。因此，FAAH的基因缺失可能使动物更容易对某些类型的疼痛敏感。需要更多的工作来确定这种变化是否可以解释FAAH抑制剂在临床试验中缺乏疗效。

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