Diester C M, Lichtman A H, Negus S S
Department of Pharmacology and Toxicology (C.M.D., A.H.L., S.S.N.), School of Pharmacy (A.H.L.), Virginia Commonwealth University, Richmond, Virginia.
Department of Pharmacology and Toxicology (C.M.D., A.H.L., S.S.N.), School of Pharmacy (A.H.L.), Virginia Commonwealth University, Richmond, Virginia
J Pharmacol Exp Ther. 2021 May;377(2):242-253. doi: 10.1124/jpet.121.000497. Epub 2021 Feb 23.
Enhanced signaling of the endocannabinoid (eCB) system through inhibition of the catabolic enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) has received increasing interest for development of candidate analgesics. This study compared effects of MAGL and FAAH inhibitors with effects of ∆9-tetrahydrocannabinol (THC) using a battery of pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to stimulate two behaviors (stretching, facial grimace) and depress two behaviors (rearing, nesting). Nesting and locomotion were also assessed in the absence of IP acid as pain-independent behaviors. THC and a spectrum of six eCB catabolic enzyme inhibitors ranging from MAGL- to FAAH-selective were assessed for effectiveness to alleviate pain-related behaviors at doses that did not alter pain-independent behaviors. The MAGL-selective inhibitor MJN110 produced the most effective antinociceptive profile, with 1.0 mg/kg alleviating IP acid effects on stretching, grimace, and nesting without altering pain-independent behaviors. MJN110 effects on IP acid-depressed nesting had a slow onset and long duration (40 minutes to 6 hours), were blocked by rimonabant, and tended to be greater in females. As inhibitors increased in FAAH selectivity, antinociceptive effectiveness decreased. PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion. THC decreased IP acid-stimulated stretching and grimace at doses that did not alter pain-independent behaviors; however, it did not alleviate IP acid-induced depression of rearing or nesting. These results support further consideration of MAGL-selective inhibitors as candidate analgesics for acute inflammatory pain. SIGNIFICANCE STATEMENT: This study characterized a spectrum of endocannabinoid catabolic enzyme inhibitors ranging in selectivity from monoacylglycerol lipase-selective to fatty acid amide hydrolase-selective in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate analgesics by effectiveness to alleviate pain-related behaviors at doses that do not alter pain-independent behaviors, with inclusion of pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives.
通过抑制分解代谢酶单酰甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶（FAAH）来增强内源性大麻素（eCB）系统的信号传导，已在开发候选镇痛药方面受到越来越多的关注。本研究使用一系列疼痛刺激、疼痛抑制和与疼痛无关的行为，比较了MAGL和FAAH抑制剂与Δ9-四氢大麻酚（THC）在雄性和雌性小鼠中的作用。腹腔注射稀乳酸（IP酸）作为一种急性内脏伤害性刺激，以刺激两种行为（伸展、面部 grimace）并抑制两种行为（竖毛、筑巢）。在没有IP酸的情况下，筑巢和运动也作为与疼痛无关的行为进行评估。评估了THC和六种从MAGL选择性到FAAH选择性的eCB分解代谢酶抑制剂，以确定它们在不改变与疼痛无关行为的剂量下减轻疼痛相关行为的有效性。MAGL选择性抑制剂MJN110产生了最有效的抗伤害感受作用，1.0mg/kg可减轻IP酸对伸展、grimace和筑巢的影响，而不改变与疼痛无关的行为。MJN110对IP酸抑制的筑巢的作用起效缓慢且持续时间长（40分钟至6小时），被利莫那班阻断，并且在雌性中往往更大。随着抑制剂FAAH选择性的增加，抗伤害感受有效性降低。PF3845是最具FAAH选择性的抑制剂，在达到破坏运动的剂量之前没有产生抗伤害感受作用。THC在不改变与疼痛无关行为的剂量下可减少IP酸刺激的伸展和grimace；然而，它并没有减轻IP酸诱导的竖毛或筑巢抑制。这些结果支持进一步考虑将MAGL选择性抑制剂作为急性炎症性疼痛的候选镇痛药。意义声明：本研究在一系列疼痛刺激、疼痛抑制和与疼痛无关的行为中，对从单酰甘油脂肪酶选择性到脂肪酸酰胺水解酶选择性的一系列内源性大麻素分解代谢酶抑制剂进行了表征，这些行为在之前的一篇配套论文中进行了药理学表征。该系列提供了一种方法，通过在不改变与疼痛无关行为的剂量下减轻疼痛相关行为的有效性来对候选镇痛药进行优先级排序，纳入疼痛抑制行为可提高转化有效性并降低对运动抑制假阳性的易感性。
