Johnson and Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, USA.
Curr Pharm Biotechnol. 2011 Oct;12(10):1644-59. doi: 10.2174/138920111798357357.
The need for new pain therapies that provide greater relief without unwanted side-effects drives the search for new drug targets. The identification of endogenous lipid ligands for the two known cannabinoid receptors (CB(1) and CB(2)) has led to numerous studies investigating the role of these endocannabinoids in pain processes. The two most widely studied endocannabinoids are anandamide (AEA; arachidonoyl ethanolamide) and 2-arachidonoylglycerol (2-AG), but there are also a number of structurally related endogenous lipid signaling molecules that are agonists at cannabinoid and noncannabinoid receptors. These lipid signaling molecules are not stored in synaptic vesicles, but are synthesized and released on-demand and act locally, as they are rapidly inactivated. This suggests that there may be therapeutic potential in modulating levels of these ligands to only have effects in active neural pathways, thereby reducing the potential for side-effects that result from widespread systemic cannabinoid receptor activation. One approach to modulate the levels and duration of action of these lipid signaling molecules is to target the enzymes responsible for their hydrolysis. The two main enzymes responsible for hydrolysis of these lipid signaling molecules are fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MGL). This article will discuss the role of the endocannabinoid system in the modulation of pain and will review the current understanding of the properties of the hydrolytic enzymes and the recent advances in developing inhibitors for these targets, with particular relevance to the treatment of pain.
新的疼痛疗法需要提供更大的缓解而没有不必要的副作用，这推动了对新药物靶点的研究。两种已知的大麻素受体（CB1 和 CB2）的内源性脂质配体的鉴定导致了许多研究调查这些内源性大麻素在疼痛过程中的作用。研究最多的两种内源性大麻素是花生四烯酸乙醇酰胺（AEA；花生四烯酰乙醇胺）和 2-花生四烯酰甘油（2-AG），但还有许多结构相关的内源性脂质信号分子是大麻素和非大麻素受体的激动剂。这些脂质信号分子不储存在突触小泡中，而是按需合成和释放，并在局部起作用，因为它们很快被失活。这表明，调节这些配体的水平可能具有治疗潜力，以使它们仅在活跃的神经通路中发挥作用，从而减少因广泛的系统大麻素受体激活而导致的副作用的可能性。调节这些脂质信号分子的水平和作用持续时间的一种方法是针对负责其水解的酶。负责这些脂质信号分子水解的两种主要酶是脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MGL）。本文将讨论内源性大麻素系统在疼痛调节中的作用，并回顾水解酶的特性以及针对这些靶点开发抑制剂的最新进展，特别是在疼痛治疗方面。
