Neural Circuits Mediating Aversion to Noxious Stimuli

与视觉和听觉等其他感觉方式不同，疼痛在阈值时是令人不愉快的。这种不愉快是一种逃避和避免组织损伤刺激的主观关联。尽管疼痛的情感动机方面的临床重要性被普遍接受，但缺乏有效的动物模型阻碍了其神经生物学基础的研究。本项目提出的研究是专门用来研究由有害刺激产生的厌恶的神经机制。我们将调整位置偏好装置来测量与后爪福尔马林注射相关的情境（条件位置厌恶或CPA）的厌恶程度。老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。在其他日子，他们将在第二个隔间中接受生理盐水。经过福尔马林调节后，减少在福尔马林相关隔间中花费的时间将作为厌恶程度的衡量标准。福尔马林引起的CPA对涉及伤害感觉的各种中枢神经系统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，P-皂苷缀合物，以选择性地破坏I层脑脊髓和脊髓丘脑神经元。如果这降低了CPA，将对大鼠进行损伤或臂旁核、脊髓丘脑靶核和皮质区被有害刺激激活的短暂失活的影响测试。待研究的丘脑区域包括腹底复合体、后丘脑/后层压板组和内丘脑/层压板区。待研究的皮质区域包括体感、前扣带和非颗粒状岛皮质。在补充研究中，将使用兴奋性化学试剂刺激与失活厌恶相关的皮质区域，以确定在没有周围有害刺激的情况下，局部神经元活动是否会引发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。

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.