Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist.
Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist.
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地佐辛（一种强效镇痛药，作为 kappa 部分激动剂和 mu 部分激动剂）的药理学特征
DOI：
10.1038/s41598-018-32568-y
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发表时间：
2018-09-20
影响因子：
4.6
通讯作者：
Wang YJ
中科院分区：
文献类型：
--
作者：
Wang YH;Chai JR;Xu XJ;Ye RF;Zan GY;Liu GY;Long JD;Ma Y;Huang X;Xiao ZC;Dong H;Wang YJ
地佐辛在中国市场正成为缓解中度至重度疼痛的主导药物。据信，地佐辛的临床疗效和在治疗过程中很少有机会引起不良事件主要归因于其对μ阿片受体的部分激动剂活性。本研究对地佐辛的药理学特性进行了全面的研究，确定地佐辛的镇痛作用是通过作用于κ和μ阿片受体的结果。我们首次发现地佐辛与μ阿片受体的结合优于与κ和δ阿片受体的结合。地佐辛本身对表达κ和μ受体的细胞中G蛋白的激活有微弱的促进作用，但在完全κ激动剂U 50，488 H和μ激动剂DAMGO存在下，地佐辛抑制了U 50，488 H和DAMGO介导的G蛋白激活，表明地佐辛是κ部分激动剂和μ部分激动剂。然后通过小鼠体内研究验证了intro结果。我们观察到κ受体拮抗剂nor-BNI和μ受体拮抗剂β-FNA预处理可显著抑制地佐辛产生的镇痛作用，表明地佐辛通过κ和μ阿片受体介导镇痛作用。当地佐辛与U_（50），488 H或吗啡合用时，地佐辛可抑制U_（50），488 H或吗啡诱导的抗伤害作用。最后，研究了κ受体激活相关的镇静副作用。我们发现地佐辛的镇静作用有限，在中等剂量时有一个上限。因此，我们的工作导致更好地了解地佐辛在体内的镇痛作用机制。
Dezocine is becoming dominated in China market for relieving moderate to severe pain. It is believed that Dezocine’s clinical efficacy and little chance to provoke adverse events during the therapeutic process are mainly attributed to its partial agonist activity at the μ opioid receptor. In the present work, we comprehensively studied the pharmacological characterization of Dezocine and identified that the analgesic effect of Dezocine was a result of action at both the κ and μ opioid receptors. We firstly found that Dezocine displayed preferential binding to μ opioid receptor over κ and δ opioid receptors. Dezocine, on its own, weakly stimulated G protein activation in cells expressing κ and μ receptors, but in the presence of full κ agonist U50,488 H and μ agonist DAMGO, Dezocine inhibited U50,488H- and DAMGO-mediated G protein activation, indicating that Dezocine was a κ partial agonist and μ partial agonist. Then the in intro results were verified by in vivo studies in mice. We observed that Dezocine-produced antinociception was significantly inhibited by κ antagonist nor-BNI and μ antagonist β-FNA pretreatment, indicating that Dezocine-mediated antinociception was via both the κ and μ opioid receptors. When co-administrating of Dezocine with U50,488 H or morphine, Dezocine was capable of inhibiting U50,488H- or morphine-induced antinociception. Finally, κ receptor activation-associated side effect sedation was investigated. We found that Dezocine displayed limited sedative effect with a ceiling effecting at a moderate dose. Thus, our work led to a better understanding of the analgesic mechanism of action of Dezocine in vivo.
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影响因子：
8.8
作者：
Liu R;Huang XP;Yeliseev A;Xi J;Roth BL
通讯作者：
Roth BL
影响因子：
64.8
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
通讯作者：
Kieffer, BL
DOI：
10.1186/1471-2210-6-3
发表时间：
2006-01-25
期刊：
BMC pharmacology
影响因子：
--
作者：
Gharagozlou, Parham;Hashemi, Ezzat;Lameh, Jelveh
通讯作者：
Lameh, Jelveh
影响因子：
7.3
作者：
ARCHER, S;PIERSO, NAK;HARRIS, LS
通讯作者：
HARRIS, LS
影响因子：
5
作者：
DUM, J;BLASIG, J;HERZ, A
通讯作者：
HERZ, A