Program in Neuroscience, Indiana University, Bloomington, IN, United States; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
Pharmacol Res. 2019 Apr;142:267-282. doi: 10.1016/j.phrs.2019.02.002. Epub 2019 Feb 7.
Activation of cannabinoid CB receptors suppresses pathological pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of fatty-acid amide hydrolase (FAAH), the major enzyme catalyzing the degradation of anandamide (AEA), an endocannabinoid, and other fatty-acid amides, suppresses pain without unwanted side effects typical of direct CB agonists. However, FAAH inhibitors have failed to show efficacy in several clinical trials suggesting that the right partnership of FAAH inhibition and pathology has yet to be identified. We compared efficacy of chronic treatments with a centrally penetrant FAAH inhibitor (URB597), a peripherally restricted FAAH inhibitor (URB937) and an orthosteric pan-cannabinoid agonist (WIN55,212-2) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Each FAAH inhibitor suppressed the development of paclitaxel-induced neuropathic pain and reduced the maintenance of already established allodynia with sustained efficacy. Tolerance developed to the anti-allodynic efficacy of WIN55,212-2, but not to that of URB597 or URB937, in each dosing paradigm. Challenge with the CB antagonist rimonabant precipitated CB-dependent withdrawal in paclitaxel-treated mice receiving WIN55,212-2 but not URB597 or URB937. When dosing with either URB597 or URB937 was restricted to the development of neuropathy, paclitaxel-induced allodynia emerged following termination of drug delivery. These observations suggest that both FAAH inhibitors were anti-allodynic rather than curative. Moreover, neither URB597 nor URB937 impeded the ability of paclitaxel to reduce breast (4T1) or ovarian (HeyA8) tumor cell line viability. In fact, URB597 and URB937 alone reduced 4T1 tumor cell line viability, albeit with low potency, and the dose matrix of each combination with paclitaxel was synergistic in reducing 4T1 and HeyA8 tumor cell line viability according to Bliss, Highest Single Agent (HSA) and Loewe additivity models. Both FAAH inhibitors synergized with paclitaxel to reduce 4T1 and HeyA8 tumor cell line viability without reducing viability of non-tumor HEK293 cells. Neither FAAH inhibitor reduced viability of non-tumor HEK293 cells in either the presence or absence of paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce paclitaxel-induced allodynia without the occurrence of CB-dependence in vivo and may, in fact, enhance the anti-tumor actions of paclitaxel in vitro.
大麻素 CB 受体的激活抑制病理性疼痛，但也会产生不良的副作用，包括耐受性和身体依赖。抑制脂肪酸酰胺水解酶 (FAAH)，该酶主要催化大麻素内源性配体 (AEA) 和其他脂肪酸酰胺的降解，可抑制疼痛而无直接 CB 激动剂的不良副作用。然而，FAAH 抑制剂在几项临床试验中未能显示出疗效，这表明 FAAH 抑制和病理学的正确结合尚未确定。我们比较了慢性治疗与中枢穿透性 FAAH 抑制剂 (URB597)、外周限制 FAAH 抑制剂 (URB937) 和正构泛大麻素激动剂 (WIN55,212-2) 在抑制紫杉醇诱导的神经病理性疼痛中的疗效。每种 FAAH 抑制剂均抑制了紫杉醇诱导的神经病理性疼痛的发展，并在已建立的痛觉过敏的维持中保持了持续的疗效。在每种给药方案中，WIN55,212-2 的抗痛觉过敏作用产生了耐受性，但 URB597 或 URB937 则没有。用 CB 拮抗剂利莫那班对紫杉醇治疗的小鼠进行挑战，引发了接受 WIN55,212-2 治疗但未接受 URB597 或 URB937 治疗的小鼠的 CB 依赖性戒断。当用 URB597 或 URB937 进行给药时，仅限于神经病变的发展，紫杉醇诱导的痛觉过敏在药物输送终止后出现。这些观察结果表明，两种 FAAH 抑制剂均具有抗痛觉过敏作用，而不是治愈作用。此外，URB597 或 URB937 均未阻止紫杉醇降低乳腺癌 (4T1) 或卵巢癌 (HeyA8) 肿瘤细胞系活力的能力。事实上，URB597 和 URB937 本身降低了 4T1 肿瘤细胞系的活力，尽管效力较低，并且根据 Bliss、最高单药 (HSA) 和 Loewe 加性模型，每种组合与紫杉醇的剂量矩阵均具有协同作用，可降低 4T1 和 HeyA8 肿瘤细胞系的活力。两种 FAAH 抑制剂均与紫杉醇协同作用，降低 4T1 和 HeyA8 肿瘤细胞系的活力，而不降低非肿瘤 HEK293 细胞的活力。在存在或不存在紫杉醇的情况下，FAAH 抑制剂均未降低非肿瘤 HEK293 细胞的活力，这表明相同的治疗并未产生非特异性细胞毒性作用。我们的结果表明，FAAH 抑制剂可减轻紫杉醇引起的痛觉过敏，而不会在体内产生 CB 依赖性，并可能实际上增强紫杉醇在体外的抗肿瘤作用。
