Contribution of the PAG to morphine tolerance

阿片类药物是治疗疼痛的最有效方法。不幸的是， 由于疾病的发展，它们的效力随着反复给药而下降 宽容的一面。这项研究的广泛长期目标是改善 通过学习如何阻止对疼痛的耐受发展来治疗疼痛 阿片类药物。尽管对吗啡耐受性进行了广泛的研究，但神经 人们对耐受性背后的机制仍然知之甚少。一个问题是， 阿片类药物作用于外周、脊髓和棘上部位，耐受性可能 在每个部位通过不同的机制进行调节。另一个问题是，那里 有几种不同类型的容差(行为、关联和 非关联性)，并且不同的机制可能是每种类型的基础。建议数 通过研究大脑调节的耐受性，研究克服了这些问题 腹外侧导水管周围灰质(VPAG)结构。VPAG是 特别感兴趣，因为它是主要下行疼痛的一部分 大脑中的调制系统和VPAG通过的神经回路 阿片类药物产生的抗伤害作用已经得到了很好的表征。此外，以前的 研究表明，耐受性发展到给药吗啡 直接进入VPAG。因此，vPAG提供了一个独特的机会 确定特定类别的神经元和潜在的机制 对阿片类药物的不同耐受性。拟议研究的第一个目标 是确定行为、关联和非关联因素 有助于VPAG介导的耐受。这将通过以下方式实现 向VPAG微量注射吗啡的环境条件 促进每一种类型的宽容。第二个目标是确定是否 耐受是由阿片类药物敏感的GABA能神经元或输出的改变引起的 神经元。PAG中的阿片类药物通过抑制GABA能产生抗伤害效应 神经元和去抑制输出神经元。如果容忍的机制 存在于对阿片类药物敏感的GABA能神经元内，那么耐受不应该 发展到微量注射直接作用于VPAG输出神经元的药物。 这一假设将通过检查对重复的耐受性来检验 VPAG内微量注射GABA拮抗剂海人酸神经兴奋剂 荷包牡丹碱和大麻素CP-55,940。拟议的研究将提供一个 为未来研究检查特定的神经机制奠定基础 不同类型的VPAG介导的耐受。从长远来看，这样的知识 应该通过允许扰乱治疗的方法来改善疼痛的治疗 公差有待开发。

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.