Neural Circuits Mediating Aversion to Noxious Stimuli

神经回路调节对有害刺激的厌恶

• 批准号: 6302762
• 负责人: HOWARD L FIELDS
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302762
• 关键词: analgesia; avoidance behavior; behavior test; behavioral /social science research tag; brain mapping; central neural pathway /tract; cues; dorsal horn; experimental brain lesion; laboratory rat; neural information processing; neural transmission; neuropeptide receptor; neurotoxins; nociceptors; pain; somesthetic sensory cortex; spinal cord mapping; stimulus /response; substance P; thalamic nuclei

In contrast to other sensory modalities such as vision and hearing, pain is, by definition, unpleasant at threshold. This unpleasantness is the subjective correlate of a drive to escape and avoid tissue damaging stimuli. Although the clinical importance of the affective-motivational aspect of pain is generally accepted, the lack of a valid animal model has hampered investigation of its neurobiological basis. The research propose din this project is specifically designed to examine the neural mechanisms of aversion produced by noxious stimuli. We will adapt the place preference apparatus to measure the magnitude of aversion to a context associated with a hindpaw formalin injection (conditioned place aversion or CPA). Rats will receive formalin in a compartment with obvious olfactory, visual and tactile cues. On alternative days they will receive saline in a second compartment. After formalin conditioning, the reduction of time spent in the formalin-associated compartment will be taken as a measure of aversiveness. The effects of formalin elicited CPA of inactivating various CNS structures implicated in nociception will be studied. In the first experiments rats will receive a substance P receptor neurotoxin, the Substance P-saporin conjugate, in the lumbar intrathecal space to selective destroy lamina I spinomesencephalic and spinothalamic neurons. If this reduces CPA, rats will be tested for the effects of lesions or transient inactivation of the parabrachial nucleus and of spinothalamic target nuclei and cortical areas activated by noxious stimuli. Thalamic areas to be studied include the Ventrobasal Complex, the posterior thalamic/posterior intralaminar group, and the medial thalamic/intralaminar region The cortical areas to be studied include the somatosensory, anterior cingulate and dysgranular insular corteces. In complementary studies, cortical areas implicated in aversion by inactivation in aversion by inactivation studies will be stimulated using excitatory chemical agents to determine if local neuronal activity can elicit CPA in the absence of a peripheral noxious stimulus. Finally, we will study the effect on formalin behaviors and CPA of reversible inactivation of descending modulatory systems.

与视觉和听觉等其他感觉方式相比，根据定义，疼痛在阈值处是令人不愉快的。这种不愉快感与逃避和避免组织损伤性刺激的驱动力主观相关。尽管疼痛的情感动机方面的临床重要性已被普遍接受，但缺乏有效的动物模型阻碍了对其神经生物学基础的研究。该项目的研究建议专门用于检查有害刺激产生厌恶的神经机制。我们将采用位置偏好装置来测量对与后爪福尔马林注射相关的环境的厌恶程度（条件性位置厌恶或 CPA）。大鼠将在具有明显嗅觉、视觉和触觉提示的隔间中接受福尔马林。在其他日子，他们将在第二个隔间中接受盐水。福尔马林调节后，在福尔马林相关隔室中花费的时间的减少将被视为厌恶程度的量度。将研究福尔马林引起的 CPA 对与伤害感受有关的各种 CNS 结构失活的影响。在第一个实验中，大鼠将在腰椎鞘内接受 P 物质受体神经毒素，即 P 物质-皂草素缀合物，以选择性破坏 I 层脊髓中脑和脊髓丘脑神经元。如果这降低了 CPA，则将测试大鼠的损伤或臂旁核和脊髓丘脑靶核和由有害刺激激活的皮质区域的短暂失活的影响。要研究的丘脑区域包括腹基底复合体、后丘脑/后层板内组和内侧丘脑/板内区域。要研究的皮质区域包括体感、前扣带回和颗粒异常岛叶皮质。在补充研究中，失活厌恶研究中涉及失活厌恶的皮质区域将使用兴奋性化学试剂进行刺激，以确定局部神经元活动是否可以在没有外周有害刺激的情况下引发 CPA。最后，我们将研究下行调节系统可逆失活对福尔马林行为和 CPA 的影响。