鞘内注射大麻素受体激动剂与右美托咪定在大鼠骨癌镇痛中的相互作用

Pharmacologic interaction between intrathecal cannabinoids and Dexmedetomidine in bone tumor pain of rats.

目的研究鞘内注射大麻素受体激动剂(WIN 55,212-2)与右美托咪定在大鼠骨癌痛模型中的镇痛作用,并了解其相互作用。方法选取120只6周雌性SD大鼠,在七氟烷麻醉下于胫骨注入大鼠乳腺癌MRMT-1细胞(1×105)建立骨癌痛模型,运用放射线和HE染色法判断骨癌形成。注入MRMT-1后第10天,将大鼠按随机数字表法分为两组:WIN 55,212-2(W组)和右美托咪定组(D组)。W组(n=40)分为对照组和WIN 55,212-2的1μg、3μg、10μg和30μg组。D组(n=32)分为对照组和右美托咪定的3μg、10μg、30μg组。通过von Frey纤维细丝测定大鼠机械缩爪阈值(MWT),观察鞘内注WIN 55,212-2和右美托咪定的镇痛效果。用等辐射分析法(n=32)分析两种药物的相互作用。结果放射线、病理学结果表明注入MRMT-1肿瘤细胞后成功建立骨癌模型,注入肿瘤细胞后大鼠MWT明显减小,产生骨癌疼痛(机械性痛觉超敏)。与对照组相比,WIN 55,212-2和右美托咪定能剂量依赖性的增加MWT(P<0.05),而等辐射分析法显示两种药物是相加作用。结论鞘内注射大麻素受体激动剂与右美托咪定有效抑制大鼠骨癌痛,两种药物的镇痛效果是相加作用。

Objective To investigate the effect of intrathecal cannabinoids(WIN55,212-2)and dexmedetomidine in bone tumor pain of rats,and also examined the drug interaction of WIN55,212-2 and dexmedetomidine.Methods Bone tumor pain was induced by injection of MRMT-1 tumor cells(1×105)into the tibia of female SD rats under sevoflurane anesthesia.The development of bone tumor was monitored by radiological study and histological sections stained with hematoxylin and eosin.At 10 days after MRMT-1 tumor cell injection,rats were randomly divided into 2 equal groups:WIN 55,212-2 group(W)and dexmedetomidine group(D).W group(n=40)was randomly divided into vehical group and WIN 55,212-2 groups(1μg,3μg,10μg and 30μg).D group(n=32)was randomly divided into vehical group and dexmedetomidine groups(3μg,10μg and 30μg).For pain assessment,a withdrawal threshold was measured using von Frey filament being applied to the tumor cell inoculation site.The effects of intrathecal WIN55,212-2 and dexmedetomidine were investigated.Isobolographic analysis was used for evaluation of pharmacologic interaction.Results Intra-tibial injection of MRMT-1 tumor cells produced a bone tumor in radiologic and pathologic findings.Also,the paw withdrawal threshold was significantly decreased(mechanical allodynia).Intrathecal WIN55,212-2 and dexmedetomidine dose-dependently increased the withdrawal threshold(P<0.05).Isobolographic analysis revealed an additive interaction after intrathecal delivery of WIN55,212-2 and dexmedetomidine.Conclusion Intrathecal WIN 55,212-2 and dexmedetomidine can reduce bone tumor-related pain behavior,and interact additively with each other.