Mechanisms of Central Sensitization in an Animal Model of Interstitial Cystitis

目前建议的总体目标是研究中枢神经系统的细胞和分子机制。 间质性膀胱炎疼痛过敏的基础敏感化(1C)。我们之前在一个 激活ERKs(细胞外信号调节激酶1)的躯体疼痛模型(后爪炎) 和2)以及由此产生的对其下游靶点Kv4.2钾通道的调制，改变了神经元 脊髓背角神经元的兴奋性及其与中枢敏感化导致疼痛的关系 躯体疼痛的过敏症。在1C小鼠模型上的初步结果显示，有害的膀胱 因此，我们 假设1C区的痛敏反应是由涉及激活的背角痛敏反应介导的 ERK的表达和Kv4.2钾通道的参与。在我们的小鼠模型中，环磷酰胺(CYP)将 用于诱导膀胱炎，而相性膀胱扩张将用作伤害性刺激 刺激引起内脏疼痛。在特定的目标1中，我们将检验背角ERK的假设 在CYP治疗的动物中，由膀胱扩张引起的激活与行为相关。我们将表演 用CYP治疗的小鼠膀胱扩张引起的ERK激活是否相关的实验 测量内脏疼痛。在特定的目标2中，我们将检验这样的假设，即中枢敏化在 在具体的AIM 3中，我们将测试 1C内脏痛模型中枢敏感化需要Kv4.2表达的假说 钾通道，这是已知的ERK1/2在背角的磷酸化靶点。这些研究 将使用分子和行为技术的组合来阐明涉及脊髓的机制 中枢敏感化导致1C中的疼痛过敏。我们在生化方面有丰富的经验。 和行为方法以及一套独特的基因敲除和转基因动物(MEKdn，ERK1-/-，Kv4.2-/-) 来进行拟议中的实验。脊髓是1C疼痛研究的新前沿。更好的 了解1C中疼痛敏化的机制可能会开辟新的治疗范式

The overall goal of the current proposal is to investigate the cellular and molecular mechanisms of central sensitization that underlies pain hypersensitivity in interstitial cystitis (1C). We previously demonstrated in a somatic pain model (hind paw inflammation) that activation of ERKs (extracellular signal-regulated kinases 1 and 2) and resultant modulation of their downstream target, the Kv4.2 potassium channel, alters neuronal excitability of spinal cord dorsal horn neurons and contributes to central sensitization leading to pain hypersensitivity in somatic pain. Preliminary results in a mouse model of 1C shows that noxious bladder distention in an inflamed bladder also evokes ERK activation in the spinal cord dorsal horn. We therefore hypothesize that pain hypersensitivity of 1C is mediated by dorsal horn pain sensitization involving activation of ERK and involvement of Kv4.2 potassium channels. In our mouse model, cyclophosphamide (CYP) will be used to induce bladder inflammation while phasic bladder distention will be used as a nociceptive stimulus to evoke visceral pain. In SPECIFIC AIM 1, we will test the hypothesis that dorsal horn ERK activation induced by bladder distention in CYP-treated animals is behaviorally relevant. We will perform experiments to test whether ERK activation evoked by bladder distention in CYP-treated mice is associated with nociceptive behaviors and increased abdominal muscle visceromotor response (VMR), an objective measurement of visceral pain. IN SPECIFIC AIM 2, we will test the hypothesis that central sensitization in a visceral pain model of 1C is mediated by activation of MEK-ERK2 signaling. IN SPECIFIC AIM 3, we will test the hypothesis that central sensitization in a visceral pain model of 1C requires the expression of Kv4.2 potassium channels, which are known phosphorylation targets of ERK1/2 in the dorsal horn. These studies will use a combination of molecular and behavioral techniques to elucidate mechanisms involved in spinal central sensitization leading to pain hypersensitivity in 1C. We have extensive experience in the biochemical and behavioral approaches and a unique set of knockout and transgenic animals (MEKdn, ERK1-/-, Kv4.2-/-) to carry out the proposed experiments. The spinal cord is a new frontier in 1C pain research. A better understanding of the mechanisms of pain sensitization in 1C may open up new therapeutic paradigms that target the central nervous system in a chronic visceral pain syndrome like 1C.