Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Pharmacology and Therapeutics, School of Medicine, NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, University Road, Galway, Ireland.
Biomed Pharmacother. 2020 Sep;129:110456. doi: 10.1016/j.biopha.2020.110456. Epub 2020 Jun 27.
Modulation of the endocannabinoid system has been shown to alleviate neuropathic pain. The aim of this study was to evaluate if treatment with paclitaxel, a chemotherapeutic agent that induces neuropathic pain, affects endocannabinoid levels at a time when mice develop paclitaxel-induced mechanical allodynia. We also evaluated the peripheral antiallodynic activity of the endocannabinoid 2-arachidonoyl glycerol (2-AG) and an inhibitor of monoacylglycerol lipase (MAGL), an enzyme responsible for 2-AG hydrolysis.
Female BALB/c mice were treated intraperitoneally with paclitaxel to induce mechanical allodynia. Levels of the endocannabinoids, N-arachidonoylethanolamine (anandamide, AEA), 2-AG, and the N-acylethanolamines (NAEs), N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which are structurally-related to AEA, in the brain, spinal cord and paw skin were measured using LC-MS/MS. Protein expression of MAGL in the paw skin was measured using Wes™. The effects of subcutaneous (s.c.) injection of 2-AG and JZL184 (a MAGL inhibitor) into the right hind paw of mice with paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer. The effects of pretreatment, s.c., into the right hind paw, with cannabinoid type 1 (CB) receptor antagonist AM251 and CB receptor antagonist AM630 on the antiallodynic effects of 2-AG were also evaluated.
The levels of 2-AG were reduced only in the paw skin of paclitaxel-treated mice, whilst the levels of AEA, PEA and OEA were not significantly altered. There was no change in the expression of MAGL in the paw skin. Administration of 2-AG and JZL184 produced antiallodynic effects against paclitaxel-induced mechanical allodynia in the injected right paw, but did not affect the uninjected left paw. The antiallodynic activity of 2-AG was antagonized by both AM251 and AM630.
These results indicate that during paclitaxel-induced mechanical allodynia there is a deficiency of 2-AG in the periphery, but not in the CNS. Increasing 2-AG in the paw by local administration of 2-AG or a MAGL inhibitor, alleviates mechanical allodynia in a CB and CB receptor-dependent manner.
内源性大麻素系统的调节已被证明可以缓解神经性疼痛。本研究的目的是评估紫杉醇（一种诱导神经性疼痛的化疗药物）治疗是否会影响内源性大麻素水平，此时小鼠会出现紫杉醇诱导的机械性痛觉过敏。我们还评估了内源性大麻素 2-花生四烯酰甘油（2-AG）和单酰基甘油脂肪酶（MAGL）抑制剂的外周抗痛觉过敏活性，MAGL 是负责 2-AG 水解的酶。
雌性 BALB/c 小鼠经腹腔注射紫杉醇诱导机械性痛觉过敏。使用 LC-MS/MS 测量大脑、脊髓和爪皮中内源性大麻素 N-花生四烯酰乙醇胺（大麻素，AEA）、2-AG 和 N-酰基乙醇胺（NAEs）N-棕榈酰乙醇胺（PEA）和 N-油酰乙醇胺（OEA）的水平，这些物质与 AEA 在结构上相关。使用 Wes™测量爪皮中 MAGL 的蛋白表达。通过动态足底感觉计评估紫杉醇诱导的机械性痛觉过敏小鼠右后爪皮下（s.c.）注射 2-AG 和 JZL184（MAGL 抑制剂）的效果。还评估了预先处理、s.c.、右后爪注射大麻素 1 型（CB）受体拮抗剂 AM251 和 CB 受体拮抗剂 AM630 对 2-AG 抗痛觉过敏作用的影响。
只有在紫杉醇处理的小鼠的爪皮中，2-AG 的水平降低，而 AEA、PEA 和 OEA 的水平没有明显改变。爪皮中 MAGL 的表达没有变化。2-AG 和 JZL184 的给药对紫杉醇诱导的机械性痛觉过敏产生了抗痛觉过敏作用，但对未注射的左爪没有影响。2-AG 的抗痛觉过敏活性被 AM251 和 AM630 拮抗。
这些结果表明，在紫杉醇诱导的机械性痛觉过敏期间，外周 2-AG 缺乏，但中枢神经系统没有。通过局部给予 2-AG 或 MAGL 抑制剂增加爪皮中的 2-AG，以 CB 和 CB 受体依赖的方式缓解机械性痛觉过敏。
