Non-opioid dynorphin A restores morphine synergy in tolerant animals

DynorphinA-(1-17)是一种内源性阿片肽，但它的一些生理、药理和行为作用似乎是通过非阿片机制介导的。其中一些作用是特别感兴趣的，因为它们可能受到dynorphin的双重调节，涉及阿片和非阿片机制。这些包括可卡因致敏的拮抗作用、胎儿垂体ACTH的释放和吗啡耐受性的减弱。在这些情况下，肌啡肽的非阿片性作用可以通过肌啡肽a -的活性来证明（2-17），它不与阿片受体结合。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的作用。这一成分的目的是阐明非阿片受体机制下的啡啡抑制吗啡耐受性。啡啡增强吗啡耐受动物的吗啡抗痛觉，抑制戒断症状。这些行为表明，dynorphin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，确定dynorphin调节阿片类药物耐受性的受体机制可能与了解dynorphin的其他非阿片类药物作用有关。dynorphin调节阿片耐受性/依赖性的机制尚不清楚，但阿片协同作用或倍增效应的研究提供了重要线索。一些研究小组已经证明，同时施用于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地添加它们的作用要有效得多。此外，一些证据表明，协同作用的减少伴随着耐受性的发展，因此这种协同作用的程度与耐受性的程度呈负相关。基于这些观察结果，我们假设dynorphin通过调节脊髓-棘上协同作用来增强吗啡在耐受动物体内的效力。为了支持这一假设，我们发现给药dynorphinA-(2-17)可以部分恢复吗啡耐受期间失去的脊髓-棘上协同作用。为了进一步探索这一现象，我们建议确定选择性m、d和k类阿片激动剂是否也表现出脊髓/棘上协同作用，如果是，在耐受动物中，dynorphinA-(2-17)对恢复这种协同作用的影响。此外，我们将评估脊髓NMDA受体在这一现象中的作用，使用选择性激动剂和拮抗剂，因为一些证据表明它们也可能调节阿片类药物的慢性作用。总的来说，这一提议旨在测试阿片类药物耐受性的新假设，并进一步了解dynorphin的非阿片类作用。

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.