A Female Specific Role of RGSz1 in Modulation of Chronic Pain

总结 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， 两性之间的关系仍然只得到部分理解。本建议的重点是研究 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的信号转导机制， （vlPAG），其选择性地调节炎性和神经性疼痛的感觉症状。 雌性老鼠G蛋白信号转导调节因子1（RGSz 1） 通过与活化的G蛋白偶联受体结合来控制G蛋白偶联受体（GPCR）的功能 亚基，包括富含高尔基体的G β z。RGSz 1负调制幅度， 参与疼痛处理调节的几种GPCR的信号转导方向， 包括血清素5 HT 1A受体。我们最近发现RGSz 1 mRNA和蛋白质 在雌性（而非雄性）小鼠的vlPAG中， 外周炎症RGSzl基因的组成性缺失或vlPAG特异性敲低 RGSz 1的表达，加剧感觉超敏反应行为，如热痛觉过敏， 机械性异常性疼痛，但它们对雄性小鼠没有影响。我们将调查 调节RGSz 1在不同的雄性和雌性vlPAG中表达的机制， 穴位后诱发周围神经损伤或炎症。我们将应用几个 在vlPAG神经元中RGSz 1的区域失活或过表达的遗传小鼠模型 子集，沿着脑生物化学，电生理学和伏安法，以了解 RGSz 1在抑郁模型下行抑制通路功能中的性别特异性作用 慢性疼痛由于RGSz 1在高尔基体的功能中起着重要作用， 应用慢性疼痛模型来了解RGSz 1对反式- 在存在和不存在疼痛的情况下的高尔基体组件。最后，我们将使用RNA 测序以了解RGSz 1对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.