长效阿片类镇痛药物镇痛与依赖分离的机制研究

Accumulating evidence suggests that the long-acting opioid analgesics, under the same analgesic effect condition, have less dependence potential and may have the characteristics of the relative separation between analgesia and dependence. On the basis of separation between analgesia and dependence of long-acting opioid analgesics, the present projects were performed to investigate the potential mechanism of separation between analgesia and dependence of long-acting opioid analgesics via resarching the difference (changes) in opioid receptor selective activation, noradrenergic function of the central locus coeruleus (physical dependence), monoamine transmitters release of the reward system in central nervous pathway (psychological dependence),neurotransmitter metabolism enzymes (monoamine oxidase)and neuronal plasticity of synaptic between two types of tool drugs with similar analgesic effect, that is, TH-030418(long-acting opioid receptor agonist)/Dihydroetorphine(short-acting opioid receptor agonist)and thienorphine (long-acting opioid receptor partial agonist)/ buprenorphine(short-acting opioid receptor partial agonist). This research can not only expand the neurobiology mechanism of drug dependence, but also provide a theoretical basis for reasonable application of opioid analgesics and develpoment of low addictive analgesics.

充分的证据显示，在产生相同镇痛效应的情况下，长效阿片类镇痛药依赖潜能低，可能具有镇痛与依赖相对分离的特性。本课题拟在进一步确证长效阿片类镇痛药镇痛与依赖相分离的基础上，选择镇痛效果相近的两组化合物，阿片受体激动剂TH-030418（长效）/二氢埃托啡（短效）、阿片受体部分激动剂噻吩诺啡（长效）/丁丙诺啡（短效）作为工具药，通过对阿片受体选择性、中枢蓝斑核（躯体依赖相关）去甲肾上腺素功能、中枢奖赏环路（精神依赖相关）的单胺递质水平、递质代谢酶（单胺氧化酶）及神经元突触可塑性变化的影响异同/程度差别等的研究，探讨长效阿片类镇痛药镇痛与依赖分离的机制。本研究的开展不仅能拓展药物依赖的神经生物学机理，而且能够为阿片类药物的合理应用和低成瘾性强止痛药的研究提供理论依据。

充分的证据显示，在产生相同镇痛效应的情况下，长效阿片类镇痛药依赖潜能低，可能具有镇痛与依赖相对分离的特性。综合本研究实验结果并结合相关文献分析，已确认THIE/BUP,TH-030418/DHE相比较，在镇痛作用相同的剂量下其依赖潜能较低，存在镇痛与依赖作用分离。THIE与TH-030418虽然是阿片受体的部分激动剂，但不形成躯体依赖，精神依赖潜能也很小，主要原因可能是对κ-受体的激动活性较强，而中枢κ-受体激动剂可以对抗μ-受体激动剂所产生的依赖反应。由于THIE与TH-030418与μ受体结合后长期占据，不能形成对μ受体的反复刺激，而阿片类药物反复刺激μ受体而导致受体水平的适应性变化是形成躯体依赖的基础，故THIE与TH-030418不表现出依赖特性，后续也证实THIE处理不影响蓝斑核内NE的含量，也不影响伏隔核和纹状体内的DA的含量；THIE可增强MAO的活性从而导致纹状体脑区DA加速代谢；THIE与阿片受体的高亲和力易化LTP的形成；THIE对学习记忆的影响远小于吗啡，这些结果均可以用来解释THIE与TH-030418的低依赖机制。而Bup及DHE于THIE及TH-030418相比对κ-受体的激动活性较弱，且与μ阿片受体结合后解离相对较快，一定程度上创造了形成依赖所必需的反复刺激受体的条件，进而表现出一定的依赖特性。本研究拓展了药物依赖的神经生物学机理，而且能够为阿片类药物的合理应用和低成瘾性强止痛药的研究提供理论依据。