CENTRAL HYPERALGESIA SYSTEMS AND ANALGESIC EFFICACY

中枢痛觉过敏系统和镇痛功效

• 批准号: 2377405
• 负责人: ERIC P WIERTELAK
• 金额: $ 8万
• 依托单位: MACALESTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-15 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377405
• 关键词: analgesics; conditioning; cues; endogenous opioid; environmental stressor; experimental brain lesion; hyperalgesia; laboratory rat; lithium; naltrexone; neuropharmacology; pain threshold; stimulus /response; taste

It is well known that the CNS contains opiate and non-opiate circuitry that acts to inhibit pain via production of analgesia. This circuitry can be activated by aversive or stressful stimuli, or environmental cues that predict impending exposure to such stimulation. Our recent evidence suggests hyperalgesia mechanisms may increase pain sensitivity in a manner complementary to analgesia mechanism activity: 1)Just as analgesia can be activated by exposure to a stressful or aversive external stimulus, central hyperalgesia mechanisms can be activated by acute exposure to an aversive internal stimulus. An aversive internal state is produced through intraperitoneal (IP) injection of lithium chloride (LiCl) or lipopolysaccharides (Endotoxin), which induce a potent cutaneous hyperalgesia as measured by the tailflick test of pain sensitivity. 2) Just as animals can learn to become analgesic in response to environmental cues that predict impending stressful or aversive external stimulation (conditioned analgesia), animals can learn to activate central mechanisms to become hyperalgesic in response to cues that predict impending internal aversive stimulation (conditioned hyperalgesia). A cue for an impending internal aversive state (emesis) was established by repeatedly pairing a novel taste with IP LiCl (conditioned taste aversion). 3)Endogenous opiates are implicated in the mediation of both the acute and learned forms of this hyperalgesia, as systemic naltrexone reverses the effect. The possibility that environmental stressors, cues for such, or analgesic agents such as the opiates may result in the simultaneous activation of both pain inhibitory and pain facilitory mechanisms has clinical implications. An understanding of these hyperalgesia systems and how they might interact with pain inhibitory processes could lead to the development of novel approaches for the control of pain and treatment of addiction. The aim of this proposal is to investigate: 1)the endogenous mechanisms underlying these central hyperalgesia systems, and 2) the possible impact of hyperalgesia system activation on the pain inhibition or analgesic efficacy produced in conditioned analgesia and acute morphine analgesia paradigms. CNS pharmacology (intrathecal and intracerebroventricular microinjection studies), lesion (electrolytic and excitotoxic lesions of specific brain sites), and behavior studies will be conducted to address basic, well defined issues central to the understanding and characterization of the mechanisms of this newly discovered circuitry.

众所周知，中枢神经系统包含阿片类和非阿片类电路 通过产生镇痛作用来抑制疼痛。该电路可以 被厌恶或压力刺激或环境暗示所激活 预测即将受到此类刺激。我们最近的证据 表明痛觉过敏机制可能以某种方式增加疼痛敏感性 与镇痛机制活动互补：1）正如镇痛一样 因暴露于压力或厌恶的外部刺激而激活， 中枢痛觉过敏机制可以通过急性暴露于 厌恶的内部刺激。厌恶的内部状态是通过以下方式产生的： 腹腔 (IP) 注射氯化锂 (LiCl) 或 脂多糖（内毒素），可诱导有效的皮肤 痛觉过敏通过疼痛敏感性的甩尾测试来测量。 2） 就像动物可以学会镇痛以应对环境一样 预测即将发生的压力或厌恶的外部刺激的线索 （条件镇痛），动物可以学习激活中枢机制 对预测即将发生的内部疼痛的线索做出反应而变得痛觉过敏 厌恶刺激（条件性痛觉过敏）。即将发生的提示 内部厌恶状态（呕吐）是通过反复配对来建立的 IP LiCl 的新口味（条件性味觉厌恶）。 3）内源性 阿片类药物与急性和习得性神经的调节有关 这种痛觉过敏的形式，因为全身纳曲酮可以逆转这种作用。 环境压力源、此类信号或镇痛剂的可能性 阿片类药物等药物可能会同时激活 疼痛抑制和疼痛促进机制均具有临床意义 影响。了解这些痛觉过敏系统以及它们如何 可能与疼痛抑制过程相互作用，可能导致 开发控制疼痛和治疗疼痛的新方法 瘾。 该提案的目的是研究：1）内生机制 这些中枢痛觉过敏系统的基础，以及 2) 可能的影响 痛觉过敏系统激活对疼痛抑制或镇痛的影响 条件镇痛和急性吗啡镇痛的疗效 范式。中枢神经系统药理学（鞘内和脑室内 显微注射研究），病变（电解和兴奋性毒性病变） 特定的大脑部位），并将进行行为研究以解决 基本的、明确定义的问题对于理解和理解至关重要 这种新发现的电路机制的表征。