Regulation of presympathetic RVLM neurons by cannabinoids

描述（由申请人提供）：这项探索性/发展性研究资助的总体目标是发现内源性大麻素（eCB）在延髓头端腹外侧（RVLM）回路中调节心血管功能的作用。中枢神经系统直接参与动脉血压的调节，主要通过交感神经系统对肾功能和腹部血管系统的作用。RVLM是介导心血管调节的中枢通路中的关键组分。前交感RVLM神经元从大脑和脊髓的多个区域接收输入，并介导许多心血管反射。高血压可能是由于交感血管神经元和抑制交感血管神经元的细胞之间的活动不平衡造成的。这一概念被描述为高血压的“中枢神经元失衡”假说。关于正常RVLM神经元调节知之甚少。G蛋白偶联大麻素1型受体（CB 1 R）在整个CNS中表达，包括RVLM。内源性大麻素（eCB），（e. G.大麻素（anandamide）作用于CB 1 R和瞬时受体电位香草素1型（TRPV 1），其也在RVLM中表达。CB 1 R和TRPV 1受体在RVLM中的功能尚不清楚。这项探索性研究将揭示RVLM介导的心血管控制中eCB作用的位点和突触机制，这一点迄今为止一直是难以捉摸的。采用免疫组织化学、体内肾神经和动脉血压（ABP）记录以及已鉴定RVLM神经元中突触电流的体外膜片钳记录的多学科方法来检验以下假设：1）CB 1 R激动剂注射到麻醉大鼠的RVLM中时，通过降低对前交感RVLM肾相关神经元的GABA能突触活性，引起交感兴奋。2)TRPV 1激动剂注射到麻醉大鼠的RVLM时会引起交感神经抑制。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。这种方法也将通过提供大麻素调节ABP的直接证据而具有临床意义，因此为高血压的治疗提供了新的治疗策略。公共卫生相关性：这项研究将揭示大麻素对涉及血压控制的脑干区域的部位和作用。脑干中的大麻素作用对于治疗高血压等疾病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.