Contribution of the PAG to morphine tolerance

阿片类药物是治疗疼痛最有效的药物。不幸的是， 它们的效力随着重复给药而降低， 宽容。这项研究的广泛的长期目标是改善 通过学习如何阻止耐受性的发展来治疗疼痛， 阿片类药物。尽管吗啡耐受性已被广泛研究，但神经系统的耐受性仍然存在。 对耐受性的机制仍知之甚少。一个问题是 阿片类药物作用于外周、脊柱和脊髓上部位， 在每个部位由不同的机制介导。另一个问题是， 有几种不同类型的容忍度（行为的，关联的， 非关联的），并且不同的机制可以是每种类型的基础。拟议 研究通过关注大脑介导的耐受性来克服这些问题， 这种结构被称为腹外侧导水管周围灰质（vPAG）。vPAG是 特别感兴趣，因为它是原发性下行疼痛的一部分 大脑中的调节系统和vPAG通过的神经回路 阿片类药物产生的抗伤害感受已经被很好地表征。此外，此前 研究表明，对吗啡的耐受性会发展， 直接进入vPAG。因此，vPAG提供了一个独特的机会， 识别神经元的特定类别和潜在的机制 不同类型的阿片类药物耐受性。拟议研究的第一个目的是 是确定行为关联和非关联因素 有助于vPAG介导的耐受性。这将通过 在环境条件下将吗啡微量注射到vPAG中 每种类型的宽容。第二个目标是确定是否 耐受性是由阿片敏感性GABA能神经元或输出的变化引起的 神经元PAG中的阿片类物质通过抑制GABA能产生抗伤害感受 神经元和去抑制输出神经元。如果宽容的机制 存在于阿片类药物敏感的GABA能神经元内，那么耐受性就不应该 发展到直接作用于vPAG输出神经元的药物的显微注射。 这一假设将通过检查重复的耐受性来检验。 向vPAG中微量注射神经兴奋剂红藻氨酸（GABA拮抗剂） 荷包牡丹碱和大麻素CP-55940。拟议的研究将提供一个 未来研究的基础，检查特定的神经机制， 不同类型的vPAG介导的耐受性。从长远来看，这样的知识 应该改善疼痛的治疗， 容忍度有待提高。

Opioids are the most effective treatment for pain. Unfortunately, their potency decreases with repeated administration because of the development of tolerance. The broad long-term objective of this research is to improve the treatment of pain by learning how to block the development of tolerance to opioids. Although morphine tolerance has been studied extensively, the neural mechanisms underlying tolerance remain poorly understood. One problem is that opioids act at peripheral, spinal, and supraspinal sites and tolerance may be mediated by different mechanisms at each site. Another problem is that there are several different types of tolerance (behavioral, associative, and non-associative) and different mechanisms may underlie each type. The proposed studies overcome these problems by focusing on tolerance mediated by a brain structure known as the ventrolateral periaqueductal gray (vPAG). The vPAG is of particular interest because it is part of the primary descending pain modulatory system in the brain and the neural circuitry through which vPAG opioids produce antinociception has been well characterized. Moreover, previous research has shown that tolerance develops to administration of morphine directly into the vPAG. Thus, the vPAG provides a unique opportunity to identify both the specific classes of neurons and the mechanisms underlying different types of tolerance to opioids. The first aim of the proposed studies is to determine whether behavioral, associative, and non-associative factors contribute to vPAG mediated tolerance. This will be accomplished by microinjecting morphine into the vPAG in environmental situations that facilitate each type of tolerance. The second aim is to determine whether tolerance is caused by a change in opioid-sensitive GABAergic neurons or output neurons. Opioids in the PAG produce antinociception by inhibiting GABAergic neurons and disinhibiting output neurons. If the mechanism for tolerance resides within opioid-sensitive GABAergic neurons, then tolerance should not develop to microinjection of drugs that act directly on vPAG output neurons. This hypothesis will be tested by examining tolerance to repeated microinjection into the vPAG of the neuroexcitant kainate, the GABA antagonist bicuculline, and the cannabinoid CP-55,940. The proposed studies will provide a foundation for future research examining specific neural mechanisms for different types of vPAG mediated tolerance. In the long term, such knowledge should improve the treatment of pain by allowing therapies that disrupt tolerance to be developed.