STUDIES ON THE ANTI-NOCICEPTIVE ACTION OF ALPHA-AGONIST DRUGS AND THEIR INTERACTIONS WITH OPIOID MECHANISMS
STUDIES ON THE ANTI-NOCICEPTIVE ACTION OF ALPHA-AGONIST DRUGS AND THEIR INTERACTIONS WITH OPIOID MECHANISMS
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DOI：
10.1111/j.1476-5381.1983.tb10504.x
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发表时间：
1983-01-01
影响因子：
7.3
通讯作者：
STARR, J
中科院分区：
文献类型：
--
作者：
BENTLEY, GA;NEWTON, SH;STARR, J
一种改良的腹部收缩试验，当扭体反应最大时，腹腔注射所用药物，用于研究各种拟交感神经药物的抗伤害性活性。在测试的那些中，可乐定是最有效的，其ID 50值在nmol范围内。（. sb.）─异丙肾上腺素，（. sbd.）-肾上腺素[epinephrine]和（. sbd.）-去甲肾上腺素（norepinephrine）的效力只差一点点。最弱的苯乙哌啶的活性仅为可乐定的1/60。 抗伤害作用可能发生在腹膜内，因为它几乎在药物注射后立即明显，并且产生的剂量远小于s.c.的有效剂量。路线α-肾上腺素受体似乎参与了反应，因为去甲肾上腺素显示立体特异性，而α-肾上腺素受体则表现出立体特异性。肾上腺素受体拮抗剂酚妥拉明和哌洛生都移动了α-肾上腺素受体的剂量-反应曲线。肾上腺素受体激动剂药物的曲线向右，通常与对照曲线平行。可乐定和羟甲唑啉的高抗伤害感受效力表明α 2-肾上腺素受体的重要性，并且哌洛生是比酚妥拉明更有效的拮抗剂。苯肾上腺素的中等效力表明α 1-肾上腺素受体也可能参与，尽管选择性α 1-拮抗剂哌唑嗪不拮抗去甲肾上腺素，并且具有其自身的抗伤害感受活性。β-的肾上腺素受体可能参与了抗伤害性反应，因为普萘洛尔拮抗异丙肾上腺素的作用，但不是可乐定。诺氟沙星是一种非常有效的吗啡拮抗剂，而酚妥拉明的作用较弱。纳洛酮对α-肾上腺素受体激动剂。用可乐定或羟甲唑啉预处理的小鼠，而不是去甲肾上腺素，对吗啡表现出非常大的交叉耐受性。吗啡预处理引起显着的脱敏本身，但很少交叉耐受可乐定或羟甲唑啉。显然，小鼠腹膜中的感觉神经具有α 2-和β-肾上腺素受体，也可能是α 1-受体。当被适当的激动剂激活时，它们可以抑制疼痛冲动的产生。在α之间存在相互作用，肾上腺素能受体和阿片受体。
A modified abdominal constriction test, whereby the drugs used are injected i.p. when the writhing response is maximal, was used to study the antinociceptive activity of various sympathomimetic drugs. Of those tested, clonidine was the most potent, with an ID50 value in the nmol range. (.sbd.)-Isoprenaline, (.sbd.)-adrenaline [epinephrine] and (.sbd.)-noradrenaline [norepinephrine] were only a little less potent. Phenylephrine, the least potent, had only about 1/60 of the activity of clonidine. The antinociceptive action may occur within the peritoneum, since it was apparent almost immediately after the drugs were injected and was produced by doses far smaller than were effective by the s.c. route. .alpha.-Adrenoceptors appear to be involved in the reaction, since noradrenaline showed stereospecificity, and the .alpha.-adrenoceptor antagonists phentolamine and piperoxan both shifted the dose-response curves of the .alpha.-adrenoceptor agonist drugs to the right, usually parallel to the control curves. The high antinociceptive potency of clonidine and oxymetazoline, indicate the importance of .alpha.2-adrenoceptors and piperoxan was a more effective antagonist than phentolamine. The moderate potency of phenylephrine suggests that .alpha.1-adrenoceptors may also be involved, although the selective .alpha.1-antagonist, prazosin, did not antagonize noradrenaline and had antinociceptive activity of its own. .beta.-Adrenoceptors may be involved in the antinociceptive response, since propranalol antagonized the effect of isoprenaline, but not that of clonidine. Piperoxan was a very effective antagonist of morphine, while phentolamine had a weaker action. Naloxone had little action against the .alpha.-adrenoceptor agonists. Mice pretreated with clonidine or oxymetazoline but not noradrenaline showed a very great cross-tolerance to morphine. Morphine pretreatment caused marked desensitization of itself, but little cross-tolerance to clonidine or oxymetazoline. Evidently sensory nerves in the mouse peritoneum have .alpha.2- and .beta.-adrenoceptors on their terminals, and possibly .alpha.1-receptors also. When activated by the appropriate agonists they may depress the generation of pain impulses. There is an interaction between the .alpha.-adrenoceptors and opioid receptors in the mouse peritoneum.