Neurogeneic Amplification of Pancreatitis Pain

描述(申请人提供)：许多胰腺炎或胰腺癌患者主诉腹痛，甚至对吗啡也有抵抗力。我们以前的研究已经确定，累及盆腔内脏的癌症患者的疼痛可以通过局限于脊髓背柱中线的神经外科病变来缓解。我们用解剖学、电生理学和行为学的方法确定，来自胰腺的感觉输入主要传递到高级脑感觉处理中心，作为突触后背柱通路的中线成分。在我们的实验室里，我们最近在Lewis近交系大鼠身上建立了一种持续性内脏疼痛的模型，这种模型在血液学和组织学上类似于人类胰腺炎。该项目的目的是研究来自胰腺的疼痛信号到达高级大脑中枢的神经通路，以及该通路的敏化如何导致持续性疼痛状态。采用多学科方法，包括行为学、电生理学和功能磁共振成像(FMRI)方法。 以下假设和具体目标是为了提高我们对慢性内脏疼痛过程的理解，以实现改进治疗的长期目标： 假设：发炎的胰腺产生的伤害性信息在脊髓中传递，通过内侧上升通路传递到更高的中枢，并在位于内侧的大脑结构中产生中枢敏化。 具体目的1是确定持续性胰腺炎时激活的伤害性感受通路。具体目的2是减少内脏伤害性通路的激活，维持在Lewis近交系大鼠持续性胰腺炎模型中的中枢敏化。 预期的长期结果是，关于内脏伤害性感受通路的信息将有助于未来确定这些涉及胰腺的毁灭性疼痛疾病的治疗靶点。

DESCRIPTION (provided by applicant): Many patients with pancreatitis or pancreatic cancer complain of abdominal pain that is resistant even to morphine. Our previous studies have determined that pain in patients with cancer involving the pelvic visceral organs is relieved by a neurosurgical lesion limited to the midline of the dorsal column of the spinal cord. We determined that sensory input from the pancreas is primarily transmitted to higher brain sensory processing centers as a midline component of the postsynaptic dorsal column pathway using anatomical, electrophysiological and behavioral methods. In our laboratory recently we have developed a model of persistent visceral pain in Lewis inbred rats that resembles human pancreatitis in blood values and histology. The purpose of the proposed project is to study the neuronal pathway by which pain signals from the pancreas reach higher brain centers and how sensitization of this pathway can lead to persistent pain states. A multidisciplinary approach is used including behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) methods. The following hypothesis and specific aims were devised to improve our understanding of chronic visceral pain processing toward the long term goal of improved therapy: HYPOTHESIS: Nociceptive information arising from the inflamed pancreas is relayed in the spinal cord, transmitted through medially ascending pathways to higher centers, and produces central sensitization in medially located brain structures. Specific Aim 1 is to determine the nociceptive pathways activated in persistent pancreatitis. Specific Aim 2 is to reduce activation in the visceral nociceptive pathways maintaining central sensitization in a persistent pancreatitis model in Lewis inbred rats. The long-term outcome expected is that information about the visceral nociceptive pathway will contribute to future identification of therapeutic targets for these devastatingly painful conditions involving the pancreas.