Regulation of presympathetic RVLM neurons by cannabinoids

描述(由申请人提供)：这项探索性/发展性研究基金的总体目标是发现内源性大麻素(ECB)在调节心血管功能的延髓头端腹外侧(RVLM)回路中的作用。中枢神经系统直接参与动脉血压的调节，主要是通过交感神经系统对肾功能和腹部血管系统的作用。RVLM是调节心血管调节的中枢通路中的重要组成部分。前交感神经RVLM神经元接受来自大脑和脊髓多个区域的输入，并调节许多心血管反射。高血压可能是由于交感血管运动神经元的活性和抑制它们的细胞之间的失衡造成的。这一概念被称为高血压的“中枢神经元失衡”假说。对正常的RVLM神经元调节知之甚少。G蛋白偶联的大麻素1型受体(CB1R)表达于整个中枢神经系统，包括RVLM。内源性大麻素(ECB)作用于CB1R和瞬时受体电位香草素1型(TRPV1)，后者也在RVLM中表达。CB1R和TRPV1受体在RVLM中的功能尚不清楚。这项探索性研究将揭示ECB在RVLM介导的心血管控制中的作用部位和突触机制，这一点到目前为止一直难以捉摸。采用免疫组织化学、在体肾神经和动脉血压(ABP)记录以及体外膜片钳记录已鉴定的RVLM神经元突触电流的多学科方法来验证以下假设：1)CB1R激动剂注入麻醉大鼠RVLM时，通过降低对交感前RVLM肾相关神经元的GABA能突触活动而引起交感兴奋。2)TRPV1激动剂注入麻醉大鼠的RVLM可引起交感神经抑制。探索这些机制将为理解大麻素对RVLM作用的细胞机制提供重要的见解。这一方法还将具有临床意义，因为它提供了大麻类药物调节ABP的直接证据，从而为高血压的治疗提供了新的治疗策略。与公共健康相关：这项研究将揭示大麻素在参与血压控制的脑干区域的位置和作用。脑干中的大麻素作用对高血压等疾病的治疗具有重要的临床意义。

DESCRIPTION (provided by applicant): The overall goal of this Exploratory/Developmental Research Grant is to discover the effects of endocannabinoids (eCB) in rostral ventrolateral medulla (RVLM) circuits that regulate cardiovascular function. The central nervous system is directly involved in regulation of arterial blood pressure, largely through actions of the sympathetic nervous system on renal function and abdominal vasculature. The RVLM is a critical component in the central pathways mediating cardiovascular regulation. Presympathetic RVLM neurons receive inputs from multiple areas of the brain and spinal cord, and mediate many cardiovascular reflexes. Hypertension may result from an imbalance between activity of sympathetic vasomotor neurons and those cells that inhibit them. This concept has been described as the "central neuron imbalance" hypothesis of hypertension. Little is known about normal RVLM neuronal regulation. The G protein-coupled cannabinoid type-1 receptor (CB1R) is expressed throughout the CNS, including the RVLM. Endogenous cannabinoids (eCB), (e. g. anandamide), act on both CB1R and transient receptor potential vanilloid type 1 (TRPV1), which are also expressed in the RVLM. The function of CB1R and TRPV1 receptors in RVLM is not known. This exploratory study will reveal the site and synaptic mechanisms of eCB actions in RVLM-mediated cardiovascular control, which have been elusive until now. A multi-disciplinary approach using immunohistochemistry, in vivo renal nerve and arterial blood pressure (ABP) recordings and in vitro patch-clamp recordings of synaptic currents in identified RVLM neurons to test the hypothesis that: 1) CB1R agonists will evoke sympathoexcitation when injected into the RVLM of anesthetized rats by decreasing GABAergic synaptic activity to presympathetic RVLM kidney-related neurons. 2) TRPV1 agonists will evoke sympathoinhibition when injected into the RVLM of anesthetized rats. Exploring these mechanisms will provide important insights about understanding the cellular mechanisms of cannabinoid actions on RVLM. This approach will also have clinical implications by providing direct evidence about the regulation of ABP by cannabinoids and therefore offer novel therapeutic strategies in the treatment of hypertension. PUBLIC HEALTH RELEVANCE: This study will reveal the site and effect of cannabinoids on a brainstem area involved in blood pressure control. Cannabinoid actions in the brainstem can have important clinical implications for the treatment of such medical conditions as hypertension.