为了检验经典大麻素1型(CB1)和2型(CB2)受体的遗传和药理学调节减弱癌症诱导的骨痛的假设,我们搜索了Medline,WebofScience和Scopus从开始到2022年7月28日的相关骨骼和非骨骼癌症研究。我们确定了29个动物和35个人类研究。在老鼠身上,汇总研究的荟萃分析显示,使用内源性大麻素AEA和2-AG(平均差异[MD]-24.83,95%置信区间[95CI]-34.89,-14.76,p<0.00001)或合成大麻素(CB)激动剂ACPA,WIN55,212-2、CP55,940(CB1/2-非选择性)和AM1241(CB2-选择性)(MD-28.73,95CI-45.43,-12.02,p=0.0008)与爪退缩频率的显著降低相关。始终如一,合成激动剂AM1241和JWH015(CB2选择性)增加了爪退缩阈值(MD0.89,95CI0.79,0.99,p<0.00001),和ACEA(CB1选择性),AM1241和JWH015(CB2选择性)减少了自发退缩(MD-4.85,95CI-6.74,-2.96,p<0。00001)在骨质溶解的雄性小鼠中。在老鼠身上,爪退缩阈值的显着增加与ACEA和WIN55,212-2(CB1/2-非选择性)的管理有关,JWH015和AM1241(CB2选择性)在有骨质溶解的女性中(MD8.18,95CI6.14,10.21,p<0.00001),用AM1241(CB2选择性)治疗会增加男性的爪退缩热潜伏期(平均差异[MD]:3.94,95CI2.13,5.75,p<0.0001),证实CB1/2配体在啮齿动物中的镇痛能力。在人类中,用医用大麻(标准化MD-0.19,95CI-0.35,-0.02,p=0.03)和植物来源的δ-9-THC(20mg)(MD3.29,CI2.24,4.33,p<0.00001)或其合成衍生物NIB(4mg)(MD2.55,95CI1.58,3.51,p<0.00001)治疗癌症患者与疼痛强度降低相关。KEGG的生物信息学验证,GO和MPO通路,小鼠的功能和过程富集分析,大鼠和人类的数据显示,CB1和CB2受体在伤害性和感官知觉的混合物中富集,炎症,免疫调节,和癌症途径。因此,我们谨慎地得出结论,CB1/2受体的药物调节剂在治疗癌症引起的骨痛中显示出希望,然而,在基因工程动物模型和癌症患者中,需要进一步评估其对骨痛的影响.
To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.