BRAINSTEM CIRCUITS IN OPIATE ANALGESIA

阿片镇痛中的脑干回路

• 批准号: 2749110
• 负责人: MARTIN W. WESSENDORF
• 金额: $ 17.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749110
• 关键词: Macaca mulatta; analgesia; antibody; brain mapping; brain stem; confocal scanning microscopy; dorsal horn; dorsal raphe nucleus; endogenous opioid; fluorescence microscopy; gamma aminobutyrate; human tissue; immunocytochemistry; neuroanatomy; opioid receptor; periaqueductal gray matter; serotonin

Opiates are potent pain-killers and are essential in clinical practice, yet it is not entirely clear how they produce analgesia. Opiate analgesia has been hypothesized to result, at least in part, from the activation of spinally projecting antinociceptive neurons located in or near nucleus raphe magnus (NRM). This activation may be partly due to a direct action of opiates on NRM and partly due to actions on the periaqueductal gray (PAG), which innervates NRM. In both NRM and PAG there is evidence for opioids activating cells by their reducing GABAergic tone; serotonergic cells in NRM have been proposed as having an antinociceptive role as well. Thus there are specific populations of cells in NRM and PAG that would be expected to be associated with opioid receptors. To date though, it has not been possible to test whether this is the case due to the technical difficulty of combining tract-tracing and immunocytochemistry with receptor-binding techniques. Recently, mRNA's encoding delta, mu, and kappa opioid receptors have been sequenced, allowing the raising of antibodies against the deduced sequences of the receptor proteins. Using these antisera in rats, we have demonstrated that some serotonergic neurons (and also non-serotonergic raphe-spinal neurons) in NRM are apposed by opioid receptor-stained varicosities; we have also found opioid receptor staining in the ventrolateral PAG, from which region many neurons project to NRC Using these same techniques, it should be possible to confirm and extend these findings in primates including (in at least some cases) humans. In the present application, we propose: 1) To determine the anatomical relationship between opioid receptors and the PAG neurons that project to NRM. 2) To determine the anatomical relationship between opioid receptors and the NRM neurons projecting to the spinal dorsal horn. 3) To determine the relationships between opioid receptors and serotonergic neurons, and between opioid receptors and GABAergic neurons. Addressing these questions will clarify how opiate analgesia occurs in humans, and may suggest strategies by which less-addictive substitutes for opioids might be developed.

阿片类药物是有效的止痛药，在临床实践中至关重要， 然而，尚不清楚它们如何产生镇痛。阿片类镇痛 已经假设至少部分地是由于激活而导致的 位于或附近核附近或附近的旋转抗伤害感受神经元的 Raphe Magnus（NRM）。这种激活可能部分是由于直接行动 NRM上的阿片类药物，部分是由于对周围灰色的作用 （PAG），它支配NRM。在NRM和PAG中，有证据表明 阿片类药物通过降低GABA能张力来激活细胞；血清素能 NRM中的细胞已被提出为具有抗伤害感受的作用 出色地。因此，NRM和PAG中有特定的细胞种群 预计将与阿片受体有关。迄今为止， 不可能测试是否由于 结合道追踪和免疫细胞化学的技术困难 使用受体结合技术。 最近，mRNA编码的Delta，MU和Kappa阿片受体已经 测序，允许对推导的抗体升高 受体蛋白的序列。在大鼠中使用这些抗血清，我们有 证明了一些血清素能神经元（以及非杂质能 NRM中的Raphe脊柱神经元）由阿片受体染色 静脉曲张；我们还发现了阿片类药物受体染色 腹外侧PAG，许多神经元从哪个区域向NRC投影 这些相同的技术，应该可以确认并扩展这些技术 灵长类动物的发现，包括（至少在某些情况下）人类。在 目前的应用，我们建议： 1）确定阿片受体和 向NRM投射的PAG神经元。 2）确定阿片类药物受体和 投射到脊柱背角的NRM神经元。 3）确定阿片受体和 血清素能神经元，阿片受体和GABA能神经元之间。 解决这些问题将阐明鸦片镇痛如何发生 人类，并可能提出策略，替代品较差的策略 对于阿片类药物可能会开发。