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首页> 外文期刊>Journal of Behavioral and Brain Science >Endorphinergic Attenuation of Distress by Concomitantly Enhancing Endogenous Opioid Release and Switching Opioid Receptor Signaling from an Excessively Excitatory to a Normal Inhibitory Mode
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Endorphinergic Attenuation of Distress by Concomitantly Enhancing Endogenous Opioid Release and Switching Opioid Receptor Signaling from an Excessively Excitatory to a Normal Inhibitory Mode

机译：通过同时增强内源性阿片样物质释放和将阿片样物质受体信号从过度兴奋转变为正常抑制模式来缓解内痛性

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The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” evoked in naive rodents shortly after acute systemic injection of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors. These symptoms result from excessive excitatory opioid receptor signaling and increased endorphin release. Pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) signaling functions of opioid receptors have utilized microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse sensory ganglia and hot-water tail-flick assays in mice. These studies led to development of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. Critical combinations of cAMP-PDE inhibitors that release endorphins plus specific agents that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled signaling were shown to attenuate hyperalgesia and distress evoked by diverse chemical stressors in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naive rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may be manifestations of a common Endorphinergic Distress Syndrome (EDS). We suggest that many distress symptoms are caused by EDS, a dysfunctional imbalance in the endogenous opioid system, consisting of abnormal endorphin levels, together with opioid receptors predominately in their excitatory mode. Therefore, concomitantly enhancing endogenous opioid release and switching excessive excitatory opioid receptor signaling to inhibitory signaling can attenuate these distress symptoms. Trials of a critically formulated oral preparation, containing both endorphin enhancers and opioid receptor switchers, have resulted in long-term anxiolytic efficacy and enhanced calm and mental clarity in large numbers of individuals with distress symptoms. These endorphinergic formulations may provide treatment for the emotional and physical distress associated with many psychiatric, neurologic, and neurodevelopmental disorders. ????????????????????????????????????????????????????????????????????????????????????????????????????????????????
机译：内源性阿片样物质系统在许多精神病，神经病学和神经发育疾病的痛苦调节中起重要作用。许多临床窘迫症状与慢性阿片类药物依赖性动物和人类的兴奋性自主神经停药作用相似，并与急性啮齿类动物在急性全身注射环状AMP-磷酸二酯酶（cAMP-）后不久诱发的“拟吗啡停药综合征”相似。 PDE）抑制剂。这些症状是由于过度的兴奋性阿片受体信号传导和内啡肽释放增加所致。阿片受体显着可塑性的双峰（兴奋性/抑制性）信号传导功能的药理分析利用了小鼠感觉神经节组织培养物中阿片类药物敏感神经元的微电极记录和小鼠热水甩尾法。这些研究导致开发了特定的化学制剂，该制剂可将类鸦片受体信号传导从过度兴奋性转变为正常抑制模式。释放内啡肽的cAMP-PDE抑制剂的关键组合以及将阿片受体从兴奋性Gs耦合转换为抑制性Gi / Go耦合信号转导的特异性药物在小鼠甩尾试验中可减轻痛觉过敏和各种化学应激因素引起的困扰。天真啮齿动物中的“准吗啡戒断综合征”以及对阿片类药物依赖的慢性动物和人的兴奋性戒断作用可能是常见的内啡肽能窘迫综合征（EDS）的表现。我们认为，许多困扰症状是由EDS引起的，EDS是内源性阿片类药物系统的功能失衡，由异常的内啡肽水平以及阿片类药物受体以兴奋性模式组成。因此，同时增强内源性阿片样物质的释放和将过多的兴奋性阿片样物质受体信号转为抑制性信号可以减轻这些困扰症状。包含内啡肽增强剂和阿片类受体切换剂的严格配制口服制剂的试验已产生长期的抗焦虑功效，并增强了许多有困扰症状的个体的镇静和精神清晰性。这些内毒素性制剂可以为与许多精神病，神经病学和神经发育障碍有关的情绪和身体困扰提供治疗。 ?????????????????????????????????????????????????????? ?????????????????????????????????????????????????????? ????????????

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