DEVELOPMENT OF A PRIMATE BEHAVIORAL NOCICEPTIVE ASSAY

在过去的几年里，科学文献中充斥着许多治疗疼痛的新方法。不幸的是，在实验室中很有希望的方法并不总是转化为更好的临床治疗。同样，用于评估这些新疗法的一些动物疼痛模型的潜在生理学和临床相关性尚未得到明确证明。造成这些差异的原因之一可能与某些镇痛治疗似乎只不同地减轻某些类型的伤害感觉有关。因此，一些标准测试可能会错过治疗疼痛类型的潜在效用，而这些疼痛类型不是由这些测试模拟的。我们发现，在确定治疗的抗伤害感受能力方面，一个重要的区别是，伤害感受反应是否以及在多大程度上是由无髓鞘的或有髓鞘的初级传入伤害感受受体的激活介导的。啮齿动物试验结果并不总是能预测临床结果，反之亦然的另一个原因可能是人类与啮齿动物之间的系统发育距离。在某些情况下，使用非人类灵长类动物模型测试潜在的治疗方法可能更能预测临床效用。因此，有必要开发一种灵长类动物实验，以区分有髓鞘或无髓鞘伤害感受器介导的伤害感觉。本提案中概述的工作目的是提供初步证据，证明在啮齿动物中确定的关于Adelta和C纤维介导的伤害感觉差异测试的原则也适用于非人灵长类动物的测试。本文描述的实验利用了由髓鞘或无髓鞘伤害感受器介导的伤害感受的敏感性差异，这些差异对不同的皮肤加热速率、局部应用神经毒素辣椒素和全身应用鸦片镇痛药吗啡的影响。这项工作的目标是开发一种灵长类动物伤害性实验，这将允许更好地预测治疗疼痛的新方法的临床应用。

Over the last several years, the scientific literature has been replete with numerous new approaches to the treatment of pain. Unfortunately, approaches that were promising in the laboratory do not always translate to better clinical treatments. Similarly, the underlying physiology and clinical relevance of some animal pain models used to evaluate these new treatments have not been clearly demonstrated. One of the reasons for these disparities may have to do with the fact that some analgesic treatments appear to differentially attenuate only some kinds of nociception. Some standard tests then, may miss the potential utility of a treatment for a pain type that is not modeled by those tests. One distinction that we have found to be important in determining antinociceptive capacity of treatments is whether, and to what extent a nociceptive response is mediated by the activation of unmyelinated or myelinated primary afferent nociceptors. Another reason that results of rodent tests do not always predict clinical outcomes and vice versa may be the phylogenetic distance between humans and rodents. It is likely that testing potential treatments using non-human primates models might be more predictive of clincial utility in some cases. Thus, there is a need for the development of a primate assay which allows for the differential assessement of nociception mediated by myelinated or unmyelinated nociceptors. The purpose of the work outlined in this proposal is to provide preliminary evidence that the principles determined in rodents with regards to differential testing of Adelta and C fiber mediated nociception are also applicable to the testing of non-human primates. The experiments described here make use of demonstrated differences in the sensitivity of nociception mediated by myelinated or unmyelinated nociceptors to different rates of skin heating, topical application of the neurotoxin capsaicin, and the systemic application of the opiate analgesic morphine. The goal of this work is to develop a primate nociceptive assay which will allow for better predictions of the clinical utility of novel approaches to the treatment of pain.