A Female Specific Role of RGSz1 in Modulation of Chronic Pain

摘要 虽然调节慢性疼痛的传递和感知的机制不同 在男性和女性之间，存在着确切的神经解剖学和分子差异 对于性别之间的关系，人们仍然只有部分了解。这项建议侧重于研究 调节雌性小鼠长期疼痛状态症状的细胞内机制。我们 已经确定了小鼠中脑导水管周围灰质腹外侧区的信号转导机制 (VlPAG)选择性地调节炎症和神经病理性疼痛的感觉症状 雌性老鼠。G蛋白信号转导调节因子-1(RGSz1) 通过与激活的GI结合来控制G蛋白偶联受体(GPCRs)的功能 亚基，包括高尔基富集区Gz。RGSz1负性调节幅度和 参与痛觉调制的几个GPCR的信号转导方向， 包括5-羟色胺5HT1a受体。我们最近发现RGSz1的mRNA和蛋白 雌性(但不是雄性)小鼠的vlPAG水平通过长期的 外周炎症。RGSz1基因的结构性缺失或vlPAG特异性敲除 RGSz1，加剧感觉过敏行为，如热痛觉过敏和 对雌性小鼠有机械性痛觉异常，但对雄性小鼠无影响。我们会调查的 RGSz1在不同性别vlPAG中表达的调控机制 穴位诱发周围神经损伤或炎症。我们将应用几个 VlPAG神经元RGSz1区域失活或过度表达的遗传性小鼠模型 以及脑生化、电生理学和伏安法，以了解 RGSz1在模型大鼠下行抑制通路功能中的性别特异性作用 慢性疼痛。由于RGSz1在高尔基体的功能中起着重要作用，威尔 应用慢性疼痛模型了解RGSz1对反式-2-羟色胺表达水平的影响 高尔基体成分在存在和没有疼痛的情况下。最后，我们将使用RNA 测序以了解RGSz1对潜在基因表达适应的影响 慢性疼痛状态。

SUMMARY While the mechanisms modulating the transmission and perception of chronic pain differ between men and women, the exact neuroanatomical and molecular differences existing between the sexes remain only partly understood. This proposal focuses on the study of intracellular mechanisms that modulate symptoms of long-term pain states in female mice. We have identified signal transduction mechanisms in the mouse ventrolateral periaqueductal gray (vlPAG) that selectively modulate sensory symptoms of inflammatory and neuropathic pain in female mice. The signal transduction modulator Regulator of G Protein Signaling-1 (RGSz1) controls the function of G protein coupled receptors (GPCRs) by binding to activated Gi subunits, including the Golgi enriched Gz. RGSz1 negatively modulates the amplitude and direction of signal transduction of several GPCRs involved in the modulation of pain processing, including the serotonin 5HT1A receptor. We recently found that RGSz1 mRNA and protein levels are dynamically regulated in the vlPAG of female (but not male) mice by long-term peripheral inflammation. Constitutive deletion of the RGSz1 gene or vlPAG-specific knockdown of RGSz1, exacerbate sensory hypersensitivity behaviors such as thermal hyperalgesia and mechanical allodynia in female mice, but they have no effect in male mice. We will investigate the mechanisms regulating the expression of RGSz1 in the male and female vlPAG at various points after the induction of peripheral nerve injury or inflammation. We will apply several genetic mouse models for regional inactivation or overexpression of RGSz1 in vlPAG neuronal subsets, along with brain biochemistry, electrophysiology and voltammetry to understand the sex-specific role of RGSz1 in the function of the descending inhibitory pathway in models of chronic pain. Since RGSz1 plays a prominent role in the function of the Golgi apparatus, will apply chronic pain models to understand the impact of RGSz1 on the expression levels of trans- Golgi components in the presence and in the absence of pain. Finally, we will use RNA Sequencing to understand the impact of RGSz1 on gene expression adaptations underlying chronic pain states.