Neural Circuits Mediating Aversion to Noxious Stimuli

与视觉和听觉等其他感官形式不同，根据定义，疼痛在临界点是令人不快的。这种不愉快是逃避和避免组织损伤刺激的驱动力的主观关联。虽然疼痛的情感激励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。这项研究提出，这个项目是专门为研究有害刺激产生厌恶情绪的神经机制而设计的。我们将调整位置偏好装置来测量厌恶的程度，以适应与后爪福尔马林注射相关的背景(条件性位置厌恶或CPA)。大鼠将在一个有明显嗅觉、视觉和触觉提示的隔间里接受福尔马林治疗。在另一天，他们将在第二个隔间接受生理盐水。在福尔马林调节后，在福尔马林相关隔间花费的时间的减少将被视为厌恶的衡量标准。福尔马林引起的CPA对与伤害性感觉有关的各种中枢神经结构失活的影响将被研究。在第一个实验中，大鼠将在腰椎鞘内间隙接受P物质受体神经毒素，即P物质-皂苷结合物，以选择性地破坏I层脊髓中脑和脊髓丘脑神经元。如果这降低了CPA，将测试大鼠臂旁核损伤或短暂失活的影响，以及伤害性刺激激活的脊髓丘脑靶核和皮质区域的影响。丘脑的研究区域包括丘脑的底核复合体、丘脑后部/后板层群和丘脑内侧/板内区。在补充性研究中，将使用兴奋性化学物质刺激通过失活的厌恶中涉及厌恶的皮质区域，以确定在没有外周伤害性刺激的情况下，局部神经元活动是否可以引发CPA。最后，我们将研究下行调节系统的可逆失活对福尔马林行为和CPA的影响。

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.