芬太尼联合布托啡诺对大鼠疼痛模型镇痛效应的药理学机制研究

Pharmacological mechanism of analgesic effect of fentanyl combined with butorphanol in rat pain model

目的研究芬太尼联合布托啡诺对大鼠疼痛模型镇痛效应的药理学机制。方法取15只SD大鼠,随机分为对照组(正常大鼠)、模型1组(疼痛模型+芬太尼给药镇痛)、模型2组(疼痛模型+布托啡诺给药镇痛),每组各5只。建立疼痛大鼠的动物模型,根据累积疼痛评分法评价大鼠疼痛行为,采用序贯法分别检测布托啡诺、芬太尼的半数有效剂量。将布托啡诺、芬太尼的半数有效剂量同时应用于大鼠,镇痛有效指征为累积疼痛评分<对照组的50%,计算布托啡诺、芬太尼期望质反应率。另取15只SD大鼠,随机分为甲组(1/4芬太尼的半数有效剂量+布托啡诺)、乙组(1/2芬太尼的半数有效剂量+布托啡诺)、丙组(3/4芬太尼的半数有效剂量+布托啡诺),每组各5只。将芬太尼1/4、1/2、3/4半数有效剂量分别联合应用布托啡诺,检测两药联合达半数有效剂量时的布托啡诺剂量,通过两药物的等效曲线评价二者合并的药效性质(拮抗、协同效应或相加作用)。结果对照组、模型1组与模型2组大鼠体重和手术前后机械痛阈值的比较,无显著差异(P>0.05)。布托啡诺镇痛的半数有效剂量为293μg/kg(196~368μg/kg),芬太尼镇痛的半数有效剂量为4.0μg/kg(2.4~5.1μg/kg)。两药半数有效剂量合并使用的观察质反应率与期望质反应率比较,无显著差异(P>0.05)。甲、乙、丙组大鼠体重和手术前后机械痛阈值的比较,无显著差异(P>0.05)。芬太尼1/4、1/2、3/4的半数有效剂量分别联合应用布托啡诺,测出两药联合达半数有效剂量时的布托啡诺剂量分别为150μg/kg(114~184μg/kg)、110μg/kg(82~130μg/kg)、94μg/kg(54~122μg/kg),进一步通过构建两药的Loewe等效曲线图,显示芬太尼与布托啡诺在一定剂量使用范围内具有协同效应,但随着芬太尼用量的增多,其与布托啡诺具有拮抗作用。结论布托啡诺+芬太尼联合镇痛时可独立产生作用,二者合并应用的药理学机制为独立联合作用。按照Loewe等效曲线图结果,提示布托啡诺与芬太尼镇痛联合作用的药效学性质(拮抗、相加或协同效应)可能与二者的用量匹配范围存在密切关系。

Objective To study the pharmacological mechanism of analgesic effect of fentanyl combined with butorphanol in rat pain model.Methods Fifteen SD rats were randomly divided into control group(normal rats),model 1 group(pain model+fentanyl analgesia)and model 2 group(pain model+butorphanol analgesia),with 5 rats in each group.The animal model of pain rat was established,and the cumulative pain scores were used to evaluate the pain behavior in rats.The median effective dose values for butorphanol and fentanyl were obtained by sequential method.The median effective doses of butorphanol and fentanyl were then applied to the rats simultaneously.The indication of effective analgesia was defined as the cumulative pain score<50%of the control group.The expected quantal response rate of butorphanol and fentanyl were calculated.Another 15 SD rats were randomly divided into group A(1/4 median effective dose of fentanyl+butorphanol),group B(1/2 median effective dose of fentanyl+butorphanol)and group C(3/4 median effective dose of fentanyl+butorphanol),with 5 rats in each group.When fentanyl at 1/4,1/2 and 3/4 median effective dose values was combined with butorphanol,the doses of the latter at combination'median effective dose value were measured.The combination's properties(synergistic,antagonistic or additive interactions)were evaluated by Loewe isobologram.Results There was no significant difference in body weight and mechanical pain threshold in control group,model 1 group and model 2 group(P>0.05).The median effective dose values for butorphanol and fentanyl were 293 g/kg(196~368μg/kg)and 4.0 g/kg(2.4~5.1μg/kg).There was no significant difference between the observed and expected quantal response rate of the combination of butorphanol and fentanyl at their median effective doses(P>0.05).There was no significant difference in body weight and mechanical pain threshold in groups A,B and C(P>0.05).When fentanyl at 1/4,1/2 and 3/4 median effective dose values was combined with butorphanol,the doses of the latter at combination'median effective dose value were 150μg/kg(114~184μg/kg),110μg/kg(82~130μg/kg)and 94 g/kg(54~122μg/kg).The Loewe isobologram indicated that fentanyl and butorphanol exhibited synergistic interactions at doses within a certain range.However,antagonistic interactions were obtained with increased fentanyl doses.Conclusion The analgesic effects of fentanyl and butorphanol were jointly independent.In combination,the drugs might be synergistic,additive,or antagonistic,depending on doses.