噻吩诺啡强镇痛和低依赖药理学特性与其激动中枢阿片受体的关系

目的从整体动物水平探讨噻吩诺啡强镇痛和低依赖的药理学特性与激动中枢阿片受体的关系。方法在小鼠乙酸扭体和热辐射甩尾模型上,利用阿片μ和κ受体特异性拮抗剂评价噻吩诺啡对阿片μ和κ受体选择性作用的强度;在小鼠躯体依赖模型上,利用κ受体特异性拮抗剂评价噻吩诺啡低依赖性是否与其激动中枢κ受体的作用有关。结果在小鼠乙酸扭体模型和热辐射甩尾模型上,脑室注射κ受体特异性拮抗剂nor-binaltorphimine(Nor-BNI)可以显著抑制噻吩诺啡的镇痛效果,使其镇痛作用分别下降28%(乙酸扭体模型)和29%(热辐射甩尾模型);μ受体特异性拮抗剂纳络肼也能显著抑制噻吩诺啡的镇痛效果,使其镇痛作用分别下降40%(乙酸扭体模型)和44%(热辐射甩尾模型),略强于κ受体拮抗剂Nor-BNI。在小鼠躯体依赖模型上,Nor-BNI伴随噻吩诺啡连续给药后纳洛酮催促,小鼠未出现跳跃等躯体依赖的戒断症状。结论噻吩诺啡在小鼠疼痛模型上的镇痛作用与其激动中枢μ和κ受体均有关。噻吩诺啡躯体依赖潜能低与其激动中枢κ受体无必然联系。

Relationship between strong antinociception and low dependence of thienorphine and its activation for central opioid receptor

AIM To study relationship between strong antinociception and low dependence of thienorphine and its activation for central opioid receptor in vivo. METHODS By evaluating antinociception of thienorphine on mouse writhing and tail flick models when pretreated with selective μ or κ receptor antagonist, respectively, to identify the contribution of analgesia by its activation for central opioid receptor subtypes. By evaluating the effect of selective κ opioid receptor antagonist on development of mice physical dependence induced by thienorphine to explain relationship between low physical dependence of thienorphine and its activation of central κ opioid receptor. RESULTSNor-binaltorphimine(Nor-BNI，a κ opioid receptor antagonist) partially inhibited antinociceptive effects of thienorphine and the inhibition rate decreased 28% on writhing model mice and 29% on tail flick model mice, respectively. Naloxonazine (a μ opioid receptor antagonist) also partially antagonized analgesic effect of thienorphine and the inhibition rate dropped 40% on writhing model mice and 44% on tail flick model mice, respectively. Thienorphine did not induce physical dependence on mice pretreated with Nor-BNI, the mice did not show jumping and other physical dependence symptoms after administration of naloxone. CONCLUSION Thienorphine can activate μ and κ opioid receptors to take its analgesic effect in vivo. There is not certain relationship between low physical dependence of thienorphine and its activation for central κ opioid receptor.