The role of spinal disinhibition in cancer induced bone pain

癌症引起的骨痛被描述为中度到重度的持续性疼痛，通常伴有一过性的骨痛 严重的疼痛“突破”(BT癌症疼痛)药物控制持续的疼痛。癌症骨痛是 主要使用缓释阿片类药物治疗，并加上快速起效的阿片类药物治疗BT癌症疼痛。这些 药物有严重的副作用，会降低患者的生活质量，这可能会将药物的剂量限制在 达到理想的疼痛控制效果。新的非阿片类药物治疗将代表着治疗的进步 癌症疼痛的症状。我们将使用癌症引起的骨痛的各种行为测量来检查多个 肿瘤性骨痛在小鼠癌性骨痛模型中的表现。退缩和条件性场所 对疼痛缓解的偏好(CPP)将被用作持续疼痛的衡量标准。触觉过敏症和 对运动触发突破性疼痛的条件性位置厌恶(CPA)将用于分析 癌症骨痛的组成部分，可能在机制上与持续性疼痛不同。在此应用程序中， 我们将检验这一假说，即GABA能抑制中间神经元的信号在 癌症引起的骨痛的背景。目标1将确定刺激脊髓GABA能的效果 抑制中间神经元对持续性疼痛、触觉超敏和运动诱发行为测量的影响 突破性疼痛。目的2确定抑制脊髓GABA能抑制性中间神经元的作用 关于持续性疼痛、触觉过敏和运动诱发的突破性疼痛的行为测量。 这些问题将使用新的光遗传和化学遗传工具进行研究，这些工具可以用于选择性地 抑制GABA能表达利用神经递质GABA和GABA传递信号的抑制性中间神经元 脊髓内的甘氨酸。拟议的研究将填补我们知识的以下空白。我们会 确定脊柱去抑制在癌症骨痛的多个临床相关方面的相对作用； 持续性疼痛、机械性超敏和突破性疼痛。我们还将描绘出正常的 抑制性GABA能信号通过丧失功能、失去联系/信号或 癌性骨痛背景下的异常兴奋信号。这样的收获使我们理解了 癌症引起的骨痛的解除抑制将允许未来使用尖端技术进行研究(例如 细胞RNAseq，蛋白质组学)揭示替代非阿片类药物开发的潜在新靶点 止痛药。

Cancer-induced bone pain is described as moderate to severe ongoing pain, often with transient episodes of severe pain that "breaks through" (BT cancer pain) medication controlling ongoing pain. Cancer bone pain is primarily treated with extended release opioids, with addition of rapid onset opioids for BT cancer pain. These drugs are associated with severe side effects that diminish patients' quality of life, and that may limit "dosing to effect" to achieve desired pain control. New non-opioid therapies would represent an advance for the treatment of cancer pain. We will use a variety of behavioral measures of cancer-induced bone pain to examine multiple aspects of tumor-induced bone pain in a mouse model of cancer bone pain. Flinching and conditioned place preference (CPP) to pain relief will be used as measures of ongoing pain. Tactile hypersensitivity and conditioned place aversion (CPA) to movement-triggered breakthrough pain will be used for analysis of components of cancer bone pain that are likely mechanistically distinct from ongoing pain. In this application, we will test the hypothesis that signaling by GABAergic inhibitory interneurons becomes excitatory in the context of cancer-induced bone pain. Aim 1 will determine the effects of stimulation of spinal GABAergic inhibitory interneurons on behavioral measures of ongoing pain tactile hypersensitivity and movement-evoked breakthrough pain. Aim 2 will determine the effects of inhibition of spinal GABAergic inhibitory interneurons on behavioral measures of ongoing pain, tactile hypersensitivity and movement-evoked breakthrough pain. These questions will be examined using new optogenetic and chemogenetic tools that can be used for selective inhibition of GABAergic expressing inhibitory interneurons that signal using the neurotransmitters GABA and glycine within the spinal cord. The proposed studies will fill the following gaps in our knowledge. We will determine the relative role of spinal disinhibition across multiple clinically relevant aspects of cancer bone pain; ongoing pain, mechanical allodynia, and breakthrough pain. We will also delineate whether the normally inhibitory GABAergic signaling undergoes disinhibition through loss of function, loss of contact/signaling, or abnormal excitatory signaling in the setting of cancer bone pain. Such gains in understanding the role of disinhibition in cancer-induced bone pain will allow for future studies using cutting edge techniques (e.g. single cell RNAseq, proteomics) to reveal potential novel targets for development of alternative non-opioid therapies for BT pain.