Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain.

IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Cannabis and Cannabinoid Research Pub Date : 2025-02-01 Epub Date: 2025-02-03 DOI:10.1089/can.2024.0088
Carl E B Rodriguez, S Olivia Vanegas, A Matthew Reck, Yasmin Schrom, Steven G Kinsey
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引用次数: 0

Abstract

Introduction: Post-surgical pain arises following a clinical operation, often persisting throughout recovery. While current treatments reduce pain, repeated use increases the probability of adverse events. monoacylglycerol lipase (MAGL) inhibition has previously been shown to produce analgesia, either through CB1 or CB2 mechanisms, dependent on the underlying pain phenotype. Thus, this study investigated the analgesic potential of inhibiting MAGL, alone and in combination with the analgesic non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium in a model of post-surgical pain. Methods: Male and female C57BL/6J mice were subjected to hindpaw incision (HPI) surgery. Mechanical allodynia, climbing, grip strength, and thermal preference were measured 24 h following HPI. The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed. Selective antagonists of CB1 and CB2 receptors were used to challenge the cannabinoid-receptor mechanism of JZL184. Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested. JZL184 was administered repeatedly to determine tolerance. Finally, hindpaw cytokines were quantified via multiplex ELISA 24 h after HPI surgery. Results: Approximately 24 h post-surgery, the MAGL inhibitors JZL184 (≥4 mg/kg) or MJN110 (≥5 mg/kg), as well as the NSAID diclofenac sodium (≥16.67 mg/kg), attenuated HPI-induced mechanical allodynia, as assessed with von Frey filaments. The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition. Similarly, LY2828360 (3 mg/kg) reduced HPI-induced allodynia. Moreover, when administered repeatedly, the anti-allodynic effects of JZL184 (8 mg/kg) persisted and did not undergo tolerance. A separate cohort was administered a sub-analgesic dose of JZL184 (1 mg/kg), diclofenac sodium (1.85 mg/kg), or both compounds concurrently. This subthreshold JZL184 and diclofenac sodium combination attenuated HPI-induced allodynia, suggesting an additive drug interaction. Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. Conclusion: These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach.

内源性大麻素联合环加氧酶抑制可减轻术后疼痛。
术后疼痛出现在临床手术之后,通常持续整个恢复过程。虽然目前的治疗方法可以减轻疼痛,但反复使用会增加不良事件发生的可能性。单酰基甘油脂肪酶(MAGL)抑制已被证明通过CB1或CB2机制产生镇痛,这取决于潜在的疼痛表型。因此,本研究在术后疼痛模型中研究了单独或联合非甾体抗炎药(NSAID)双氯芬酸钠抑制MAGL的镇痛潜力。方法:雄性和雌性C57BL/6J小鼠后爪切开(HPI)手术。机械异常性疼痛、攀爬、握力和热偏好在HPI后24小时进行测量。评估了MAGL抑制剂(不可逆MAGL抑制剂[JZL184]和选择性MAGL抑制剂[MJN110])和非甾体抗炎药双氯芬酸的剂量依赖性抗异动作用,以及MAGL和环氧合酶(COX)联合抑制的加性潜力。使用CB1和CB2受体的选择性拮抗剂挑战JZL184的大麻素受体机制。同样地,我们测试了cb2选择性激动剂(LY2828360)的抗变动力作用。反复给药JZL184测定耐受性。最后,在HPI手术后24 h,通过多重ELISA定量检测后肢细胞因子。结果:术后约24小时,经von Frey纤维评估,MAGL抑制剂JZL184(≥4mg /kg)或MJN110(≥5mg /kg)以及非甾体抗炎药双氯芬酸钠(≥16.67 mg/kg)可减轻hpi诱导的机械异常性疼痛。JZL184 (40 mg/kg)的抗异动作用被CB2拮抗剂SR144528 (3 mg/kg)预处理阻断,而cb1选择性拮抗剂利莫那班(SR141716A;3 mg/kg),提示cb2通过MAGL抑制抗异位性痛的机制。同样,LY2828360 (3mg /kg)减少hpi诱导的异常性疼痛。此外,当反复给药时,JZL184 (8 mg/kg)的抗异动作用持续存在且不产生耐受性。另一组受试者同时服用亚镇痛剂量的JZL184 (1mg /kg)、双氯芬酸钠(1.85 mg/kg)或两种化合物。这种阈下JZL184和双氯芬酸钠联合使用减轻了hpi诱导的异位性疼痛,表明药物相互作用是加性的。最后,HPI本身增加了促炎细胞因子水平,尽管行为上评估了抗异常性疼痛,但MAGL抑制并未改变促炎细胞因子水平。结论:这些数据支持同时靶向内源性大麻素和COX酶作为潜在的术后疼痛管理方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cannabis and Cannabinoid Research
Cannabis and Cannabinoid Research PHARMACOLOGY & PHARMACY-
CiteScore
6.80
自引率
7.90%
发文量
164
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