Non-opioid dynorphin A restores morphine synergy in tolerant animals

描述：(申请人的摘要)强啡肽A-(1-17)是一种内源性阿片肽，但其一些生理、药理和行为作用似乎是通过非阿片机制介导的。 其中一些效应特别令人感兴趣，因为它们可能受到强啡肽的双重调节，涉及阿片类药物和非阿片类药物机制。 这些包括拮抗可卡因致敏作用、胎儿垂体释放 ACTH 以及减弱吗啡耐受性。 在这些病例中，强啡肽的非阿片类作用是通过强啡肽 A-(2-17) 的活性来证明的，它不与阿片类受体结合。然而，经典阿片受体激动剂和拮抗剂的实验也表明阿片受体在这些现象中发挥着作用。 该组件的目的是阐明强啡肽减弱吗啡耐受性的非阿片受体机制。 强啡肽可增强吗啡耐受动物的吗啡镇痛作用，并抑制戒断症状。 这些作用表明强啡肽可能对需要长期缓解疼痛的患者以及阿片类药物成瘾者的治疗有用。 此外，强啡肽调节阿片类药物耐受性所涉及的受体机制的识别可能与理解强啡肽的其他非阿片类药物作用有关。强啡肽调节阿片类药物耐受/依赖性的机制尚不清楚，但阿片类药物协同作用或倍增效应的研究提供了重要线索。几个研究小组已经证明，同时给予脊柱和脊柱上部位的阿片类激动剂比单独在每个部位简单叠加其效果所预期的效果要有效得多。 此外，一些证据表明，协同作用的降低伴随着耐受性的发展，因此这种协同作用的程度与耐受程度成反比。 基于这些观察，我们假设强啡肽对吗啡耐受动物的效力增强是通过脊髓-脊髓上协同作用的调节来实现的。 为了支持这一假设，我们发现强啡肽A-(2-17)的施用部分恢复了吗啡耐受期间丧失的脊髓-脊髓上协同作用。 为了进一步探讨这一现象，我们建议确定选择性 m、d 和 k 阿片类激动剂是否也表现出脊髓/脊髓上协同作用，如果是的话，强啡肽 A-(2-17) 在耐受动物中恢复这种协同作用的作用。 此外，我们将使用选择性激动剂和拮抗剂评估脊髓 NMDA 受体在这一现象中的作用，因为一些证据表明它们也可能调节阿片类药物的慢性影响。 总体而言，该提案旨在测试阿片类药物耐受性的新假设，并进一步了解强啡肽的非阿片类药物作用。

DESCRIPTION: (Applicant's Abstract) DynorphinA-(1-17) is an endogenous opioid peptide, but some of its physiological, pharmacological and behavioral effects appear to be mediated through non-opioid mechanisms. Several of these effects are of particular interest, because they may be subject to dual regulation by dynorphin, involving both opioid and nonopioid mechanisms. These include antagonism of cocaine sensitization, release of ACTH from the fetal pituitary, and attenuation of morphine tolerance. The nonopioid contribution of dynorphin in each of these cases is demonstrated by the activity of dynorphinA-(2-17), which does not bind to opioid receptors. Yet experiments with classical opioid agonists and antagonists also indicate a role for opioid receptors in each of these phenomena. The purpose of this component is to elucidate the nonopioid receptor mechanisms underlying dynorphin attenuation of morphine tolerance. Dynorphin potentiates morphine antinociception in the morphine tolerant animal, and suppresses withdrawal symptoms. These actions suggest that dynorphin could be useful for patients requiring long term pain relief as well as for treatment of opioid addicts. In addition, identification of the receptor mechanisms involved in dynorphin modulation of opioid tolerance is likely to be relevant to understanding dynorphin's other nonopioid actions. The mechanism by which dynorphin modulates opioid tolerance/dependence is not known, but an important clue is provided by studies of opioid synergism, or multiplicative effects. Several groups have demonstrated that opioid agonists administered simultaneously to both spinal and supraspinal sites are much more potent than would be expected from a simple addition of their effects at each site alone. Moreover, some evidence indicates that a decrease of synergism accompanies tolerance development, so that the degree of this synergism is inversely correlated with the degree of tolerance. Based on these observations, we have hypothesized that dynorphin's enhancement of morphine's potency in tolerant animals is exerted through a regulation of spinal--supraspinal synergism. In support of this hypothesis, we have found that administration of dynorphinA-(2-17) partially restores the spinal-supraspinal synergism that is lost during morphine tolerance. To explore this phenomenon further, we propose to determine whether spinal/supraspinal synergism is also exhibited by selective m, d and k opioid agonists, and if so, the effect of dynorphinA-(2-17) on restoring it in the tolerant animals. In addition, we will evaluate the role of spinal NMDA receptors in this phenomenon, using selective agonists and antagonists, as some evidence indicates that they may also modulate the chronic effects of opioids. Overall, this proposal is designed to test a novel hypothesis of opioid tolerance, as well as obtain further insight into the nonopioid actions of dynorphin.