Selective antagonism of opioid analgesia by a sigma system.
Selective antagonism of opioid analgesia by a sigma system.
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发表时间：
1994-12
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通讯作者：
C. Chien;G. Pasternak
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作者：
C. Chien;G. Pasternak
(+)喷他佐辛与其(-)-异构体一样有效地拮抗吗啡的镇痛作用，排除了阿片受体的作用机制，并提示Sigma-1受体的作用。全身性(+)五唑碱也可逆转脊髓上或脊髓吗啡的止痛作用。1，3-二(2-甲苯基)胍是一种不具有明显阿片受体亲和力的Sigma配体，可拮抗吗啡的镇痛作用。氟哌啶醇对Sigma和D2受体都有很高的亲和力，但不能被D2选择性拮抗剂(-)舒必利逆转，后者在Sigma位点缺乏活性。抗阿片类药物西格玛系统在音调上是活跃的。氟哌啶醇，但不是(-)舒必利，使吗啡ED50减少近2倍。抗阿片系统只调节MU的止痛。与止痛不同，(+)五唑碱不影响吗啡对胃肠传输的抑制或致死性。(+)戊唑西汀也以氟哌啶醇敏感的方式通过sigma机制拮抗Kappa 1、Kappa 3和Delta的镇痛作用。(-)舒必利不起作用。单独使用氟哌啶醇时，Kappa 1、Kappa 3和Delta的镇痛作用比吗啡更显著，这表明Sigma系统对所有阿片类止痛系统都是有效的。Sigma系统是kappa受体敏感性的一些品系差异的原因。与CD-1小鼠不同，BALB-C小鼠对kappa 1制剂U50,488H和kappa 3止痛剂纳洛酮苯甲酰肼相对不敏感。用氟哌啶醇阻断Sigma系统可以消除这些菌株的差异。综上所述，Sigma-1系统在功能上拮抗阿片类药物的镇痛作用，而不影响吗啡对胃肠道转运或致死性的影响。抗阿片类药物西格玛系统在音调上是活跃的，在对抗kappa止痛方面比u更活跃。
(+)Pentazocine antagonizes morphine analgesia as potently as its (-)-isomer, ruling out an opioid receptor mechanism of action and suggesting, which suggests a role for sigma 1 receptors. Systemic (+) pentazocine also reverses supraspinal or spinal morphine analgesia. 1,3-Di(2-tolyl)guanidine, a sigma ligand with no appreciable opioid receptor affinity, antagonizes morphine analgesia. The actions of both (+)pentazocine and 1,3-di(2-tolyl)guanidine are reversed by haloperidol, which has high affinity for both sigma and D2 receptors, but not by the D2-selective antagonist (-)sulpiride, which lacks activity at sigma sites. The antiopioid sigma system is tonically active. Haloperidol, but not (-)sulpiride, decreases morphine ED50 almost 2-fold. The antiopioid system modulates only mu analgesia. Unlike analgesia, (+)pentazocine does not influence morphine's inhibition of gastrointestinal transit or lethality. (+)Pentazocine also antagonizes kappa 1, kappa 3 and delta analgesia through sigma mechanisms in a haloperidol-sensitive manner. (-)Sulpiride is inactive. Alone, haloperidol enhances kappa 1, kappa 3 and delta analgesia more dramatically than morphine, which indicates that the sigma system is active against all opioid analgesic systems. Sigma systems are responsible for some strain differences in kappa receptor sensitivity. Unlike CD-1 mice, BALB-C mice are relatively insensitive toward the kappa 1 agent U50,488H and the kappa 3 analgesic naloxone benzoylhydrazone. Blockade of the sigma system with haloperidol eliminates these strain differences. In conclusion, sigma 1 systems functionally antagonize opioid analgesia without affecting morphine's effects on gastrointestinal transit or lethality. The antiopioid sigma system is tonically active and is more active against kappa analgesia than mu.(ABSTRACT TRUNCATED AT 250 WORDS)