AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
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AM-251和Rimonabant作为MU-Apioid受体的直接拮抗剂：对阿片类/大麻素相互作用研究的影响。
DOI：
10.1016/j.neuropharm.2012.06.046
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发表时间：
2012-10
影响因子：
4.7
通讯作者：
Prather PL
中科院分区：
文献类型：
--
作者：
Seely KA;Brents LK;Franks LN;Rajasekaran M;Zimmerman SM;Fantegrossi WE;Prather PL
MU-阿片和CB1-大麻素激动剂产生镇痛作用；然而，副作用限制了这两类药物的使用。同时使用小剂量的MU和CB1激动剂所产生的相加或协同效应可能产生副作用较少的镇痛作用。Mu-阿片受体(MORs)和CB1受体(CB1Rs)之间的相互作用可能产生协同作用。AM-251和利莫那班是CB1R拮抗剂/反向激动剂，用于验证阿片-大麻素相互作用，被认为是选择性地作用于CB1R。因此，这些拮抗剂在MORS中直接作用的可能性很少被考虑。本研究确定AM-251和/或利莫那班是否直接结合和调节MORS的功能。令人惊讶的是，AM-251和利莫那班，但不是第三个CB1R反向激动剂AM-281，与人MORS具有中纳米分子亲和力，亲和力等级顺序为AM-251(251 NM)和利莫那班(652 NM)>；AM281(2135 NM)。AM-251和利莫那班(而不是AM-281)也竞争性拮抗吗啡诱导的CHO-hMOR细胞匀浆中G蛋白的激活(Kb分别为719和1310 nM)。AM-251和利莫那班可阻断吗啡对cAMP生成的抑制作用，而只有AM-251能引起慢性吗啡暴露的CHO-hMOR细胞cAMP的反弹。AM-251和利莫那班(10 mg/kg)可减弱吗啡的镇痛作用，而相同剂量的AM-281作用不明显。因此，除了CB1R的高亲和力外，AM-251和利莫那班与MORS具有中纳摩尔亲和力，在较高剂量时可能通过直接拮抗MORS而影响吗啡的镇痛作用。当通过药理学方法在CB1基因敲除小鼠和野生型小鼠中检查CB1/MOR相互作用时，这些拮抗剂的这种CB1非依赖性作用可能导致报告的不一致。
Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (Ki) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (Kb = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent actions of these antagonists may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.
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影响因子：
56.9
作者：
Ledent, C;Valverde, O;Parmentier, M
通讯作者：
Parmentier, M
影响因子：
4.7
作者：
Fattore, L;Spano, S;Fratta, W
通讯作者：
Fratta, W
影响因子：
5
作者：
Gardner, A;Mallet, PE
通讯作者：
Mallet, PE
DOI：
10.1111/j.1432-1033.1996.0704p.x
发表时间：
1996-05-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Bouaboula, M;PoinotChazel, C;Casellas, P
通讯作者：
Casellas, P
影响因子：
3.5
作者：
Hojo, Minoru;Sudo, Yuka;Uezono, Yasuhito
通讯作者：
Uezono, Yasuhito