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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >ULTRA-LOW CONCENTRATIONS OF NALOXONE SELECTIVELY ANTAGONIZE EXCITATORY EFFECTS OF MORPHINE ON SENSORY NEURONS, THEREBY INCREASING ITS ANTINOCICEPTIVE POTENCY AND ATTENUATING TOLERANCE DEPENDENCE DURING CHRONIC COTREATMENT
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ULTRA-LOW CONCENTRATIONS OF NALOXONE SELECTIVELY ANTAGONIZE EXCITATORY EFFECTS OF MORPHINE ON SENSORY NEURONS, THEREBY INCREASING ITS ANTINOCICEPTIVE POTENCY AND ATTENUATING TOLERANCE DEPENDENCE DURING CHRONIC COTREATMENT

机译：吗啡对感觉神经元的纳洛酮选择性拮抗兴奋作用的超低浓度，从而提高了其在慢性共处理过程中的抗认知能力并降低了耐受性

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Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions, Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca2+-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening, The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists, Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists, These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability, Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays. [References: 66]
机译：皮摩尔浓度超低的阿片样物质拮抗剂纳洛酮（NLX）和纳曲酮（NTX）对小鼠背根神经节（DRG）神经元的兴奋性阿片受体功能具有显着的拮抗作用，而较高的纳摩尔浓度则拮抗兴奋性和抑制性阿片样物质功能，预处理皮摩尔浓度的任一拮抗剂对天真伤害感受型DRG神经元的阻滞，抑制了皮摩尔-纳摩尔吗啡引起的动作电位持续时间（APD）的Ca2 +依赖性成分的兴奋性延长，并揭示了抑制性APD缩短，本研究提供了一种细胞机制解释了以前的报道，低剂量的NLX和NTX矛盾地增强了吗啡和其他阿片类激动剂的镇痛作用，而不是减弱了这种作用。此外，DRG神经元与微摩尔吗啡加皮摩尔NLX或NTX的长期联合治疗阻止了（i）的发展抑制性APD缩短效应的耐受性高浓度吗啡和（ii）对纳摩尔NLX的兴奋性APD延长作用以及超低（飞摩尔-皮摩尔）浓度的吗啡和其他阿片类激动剂的超敏感性，这些体外研究表明，超低吗啡选择性阻断吗啡兴奋作用的NLX或NTX剂量不仅可以增强吗啡和其他双峰作用的阿片类激动剂的镇痛作用，而且还可以显着减轻它们的依赖性，随后的相关研究表明，用吗啡加超剂量对小鼠进行联合治疗实际上，低剂量NTX在甩尾试验中确实增强了吗啡的抗伤害感受能力，并减弱了慢性以及急性，身体依赖性试验中戒断症状的发展。 [参考：66]

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