Non-opioid dynorphin A restores morphine synergy in tolerant animals

描述：(申请人摘要)强啡肽A-(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。这些影响中有几个特别令人感兴趣，因为它们可能受到强啡肽的双重调节，涉及阿片和非阿片机制。这些包括可卡因敏化的拮抗作用，胎儿脑下垂体ACTH的释放，以及吗啡耐受性的减弱。强啡肽A-(2-17)的活性不与阿片受体结合，表明强啡肽在这些病例中对非阿片类药物的贡献。然而，用经典的阿片激动剂和拮抗剂进行的实验也表明，阿片受体在这些现象中都发挥了作用。该成分的目的是阐明强啡肽减弱吗啡耐受的非阿片受体机制。强啡肽增强吗啡耐受动物的吗啡抗伤害性，并抑制戒断症状。这些行动表明，强啡肽可能对需要长期止痛的患者以及阿片成瘾患者的治疗有用。此外，识别强啡肽调节阿片耐受的受体机制可能与了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一条重要线索。几个小组已经证明，同时对脊髓和脊髓上部位给予阿片激动剂比仅在每个部位简单地增加它们的作用所预期的效果要强得多。此外，有证据表明，随着耐受性的发展，协同作用的减弱，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，我们假设强啡肽增强耐受动物的吗啡效力是通过调节脊髓-脊髓上的协同作用而起作用的。为了支持这一假设，我们发现给予强啡肽A-(2-17)可以部分恢复在吗啡耐受过程中失去的脊髓-棘上协同作用。为了进一步探讨这一现象，我们建议确定选择性的m、d和k阿片激动剂是否也表现出脊髓/脊髓上的协同作用，如果是，那么强啡肽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来评估脊髓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，这一建议旨在检验阿片类药物耐受的新假说，并进一步深入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.