Noradrenergic Synaptic Function in the Bed Nucleus of the Stria Terminalis Varies in Animal Models of Anxiety and Addiction

Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction.     

Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury

Pontospinal noradrenergic neurons form part of an endogenous analgesic system that suppresses acute pain, but there is conflicting evidence about its role in neuropathic pain. We investigated the chronology of descending noradrenergic control during the development of a neuropathic pain phenotype in rats following tibial nerve transection (TNT). A lumbar intrathecal cannula was implanted at the time of nerve injury allowing administration of selective α-adrenoceptor (α-AR) antagonists to sequentially assay their effects upon the expression of allodynia and hyperalgesia. Following TNT animals progressively developed mechanical and cold allodynia (by day 10) and subsequently heat hypersensitivity (day 17). Blockade of α₂-AR with intrathecal yohimbine (30 μg) revealed earlier ipsilateral sensitization of all modalities while prazosin (30 μg, α₁-AR) was without effect. Established allodynia (by day 21) was partly reversed by the re-uptake inhibitor reboxetine (5 μg, i.t.) but yohimbine no longer had any sensitising effect. This loss of effect coincided with a reduction in the descending noradrenergic innervation of the ipsilateral lumbar dorsal horn. Yohimbine reversibly unmasked contralateral hindlimb allodynia and hyperalgesia of all modalities and increased dorsal horn c-fos expression to an innocuous brush stimulus. Contralateral thermal hyperalgesia was also reversibly uncovered by yohimbine administration in a contact heat ramp paradigm in anaesthetised TNT rats. Following TNT there is an engagement of inhibitory α₂-AR-mediated noradrenergic tone which completely masks contralateral and transiently suppresses the development of ipsilateral sensitization. This endogenous analgesic system plays a key role in shaping the spatial and temporal expression of the neuropathic pain phenotype after nerve injury.     

Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients

Objective To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine.Design Prospective, controlled, trial.Setting Neurosciences critical care unit.Patients Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP).Intervention Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrationsMeasurements and results Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r ²=0.431), and systemic vascular resistance index (r ²=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of ~ 50 nM/l (corresponding to an infusion rate of ~ 15 g·kg^-1·min^-1).Conclusions Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.     

神经内分泌激素活性在心力衰竭中的作用研究

目的探讨心力衰竭患者神经内分泌激素的活性变化及其临床意义。方法随机选取2011年1月至2012年6月的79例心力衰竭患者作为研究对象,分别测定其治疗前后去甲肾上腺素（NE）、神经肽Y（NPY）、心钠素（ANP）及降钙素基因相关肽（CGRP）的水平,同时取36例健康献血者作为对照组,测定项目同实验组。结果心力衰竭患者实施治疗前,各项检测指标显著高于正常对照组（P〈0．05）。治疗后各项检测指标均较治疗前显著降低（P〈0．05）,与对照组相比略高,但差异无统计学意义（P〉0．05）。结论心力衰竭患者神经内分泌激素水平明显升高,其活动性与疾病预后密切相关。部分检测项目可作为评估心力衰竭的参考指标。     

Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: A retrospective cohort study

Purpose

There are little data regarding the discontinuation of vasoactive medications in patients recovering from septic shock. We designed this retrospective cohort study to evaluate the incidence of hypotension based on the order of removal of norepinephrine (NE) and vasopressin (AVP) in patients receiving concomitant NE and AVP infusions for the treatment of septic shock.

Materials and Methods

Consecutive patients receiving concomitant NE and AVP infusions for septic shock admitted to the intensive care units of a tertiary care academic medical center were evaluated.

Results

Of 50 included patients, the first vasoactive medication discontinued was NE in 32 patients and AVP in 18 patients. The groups had similar Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores at shock onset and at the time of discontinuation of the first agent. Five patients who had NE discontinued first (16%) versus 10 patients who had AVP discontinued first (56%) developed hypotension within 24 hours (unadjusted relative risk, 3.6; 95% confidence interval, 1.5-4.5; P = .008). In a multivariate analysis, only discontinuation of AVP first was independently associated with hypotension (adjusted relative risk, 5.9; 95% confidence interval, 1.7-21.0; P = .006).

Conclusions

Discontinuation of AVP before NE may lead to a higher incidence of hypotension in patients recovering from septic shock receiving concomitant AVP and NE.     

低温盐水灌注对猪心肺复苏后肝肾核转录因子-κB的影响

目的 研究去甲肾上腺素(NE)诱导的高血压灌注状态对猪心肺复苏成功后肝脏功能及组织形态的影响.方法 诱导猪出现心室纤颤4 min后给予标准心肺复苏,自主循环恢复(ROSC)后应用NE干预治疗,然后按随机数字表法将ROSC的10只猪均分为两组;高血压组维持平均动脉压(MAP)为基础血压的130%,正常血压组维持MAP为基础血压水平,均予以10 ml·kg~(-1)·h~(-1)的生理盐水补液;同时监测血流动力学;分别于基础状态及ROSC后10 min、2 h、4 h抽血检测血清天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)和乳酸脱氢酶(LDH);于ROSC后24 h处死动物,取肝脏组织检测Na~+-K~+-ATP酶和Ca~(2+)-ATP酶活性;光镜和电镜下观察肝组织病理改变.结果 高血压组在ROSC后心率、MAP、心排血量和冠状动脉灌注压均显著高于正常血压组,氧摄取率较正常血压组降低.与正常血压组同时间点比较,高血压组血清AST于ROSC后2 h、4 h显著降低[ROSC后2 h:(110.5±12.1)U/L比(141.8±8.1)U/L,ROSC后4 h:(118.2±14.1)U/L比(175.0±14.3)U/L,均P＜0.05],ROSC后4 h LDH显著降低[(18.1±1.9)μmol·s~(-1)·L~(-1)比(20.7±1.9)μmol·s~(-1)·L~(-1),P＜0.05],而两组间ROSC后各时间点ALT变化不明显.高血压组肝脏ATP酶活性[Na~+-K~+-ATP酶:(2.054±0.716)U,Ca~(2+)-ATP酶:(1.889±0.450)U]较正常血压组Na~+-K~+-ATP酶:(3.274±0.710)U,Ca2+-ATP酶:(2.746±0.788)U]有所下降,但并无显著差异(均P＞0.05).与正常血压组相比,高血压组肝脏细胞水肿、坏死,炎性细胞浸润以及线粒体结构破坏程度较轻.结论 NE诱导的高血压灌注状态对维持ROSC后血流动力学稳定及氧代谢平衡有重要作用,对ROSC后肝脏功能及组织形态都有一定的保护作用.     

腰椎旁神经阻滞联合全凭静脉全身麻醉对髋关节置换术患者血流动力学、应激反应、术后苏醒的影响

目的 观察腰椎旁神经阻滞联合全凭静脉全身麻醉对髋关节置换术患者血流动力学、应激反应、术后苏醒的影响.方法 选取2018年1月—2019年8月我院收治的行髋关节置换术患者115例,根据手术麻醉方法 的不同分为观察组60例和对照组55例,观察组予腰椎旁神经阻滞联合全凭静脉全身麻醉,对照组仅予全凭静脉全身麻醉.比较两组麻醉...     

A comparison of epinephrine and norepinephrine in critically ill patients

Objective  To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients. Design  Prospective, double-blind, randomised-controlled trial. Setting  Four Australian university-affiliated multidisciplinary ICUs. Patients and participants  Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately. Interventions  Blinded infusions of epinephrine or norepinephrine to achieve a MAP ≥70 mmHg for the duration of ICU admission. Measurements  Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8–70.4 h) with epinephrine compared to 40.0 h (IQR 14.5–120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69–1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59–1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62–1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality. Conclusions  Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients. This study was presented at the Annual Congress of the European Society of Intensive Care Medicine in Berlin on October 10 2007. The presentation received the International Sepsis Forum prize for best abstract and paper. This study has been published in abstract form: Myburgh J.A., Higgins A., Jovanovska A., Lipman J., Ramakrishnan N., Santamaria J and the CAT Study Investigators. (2007). A comparison of epinephrine and norepinephrine on reversal of shock. Intensive Care Medicine 33 (Supplement 2): S197. Trial registration: The study was registered with Current Controlled Studies: ISRCTN number 92846592.     

Treatment of impaired perfusion in septic shock

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment. Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.     

Release of endogenous 5-hydroxytryptamine from resting and stimulated enteric neurons

Physiological and biochemical evidence has indicated that there may be serotoninergic neurons in the enteric nervous system. A critical step in the identification of a neurotransmitter is the demonstration of the release of the substance upon nerve stimulation. We now report the release of endogenous 5-hydroxytryptamine from enteric neurons. Segments of guinea-pig small intestine were everted and perfused in vitro through the newly created serosal lumen. Tests with [³H]5-hydroxytryptamine revealed the existence of a tissue barrier preventing diffusion of mucosal (enteroendocrine cell) 5-hydroxytryptamine into the perfusate; thus, all 5-hydroxytryptamine in the perfusate was of neural origin. The gut was stimulated electrically. 5-Hydroxytryptamine in the perfusate and in the myenteric plexus was assayed by a specific radioenzymatic method. 5-Hydroxytryptamine was present in the myenteric plexus; it was released into the perfusate spontaneously and the release was enhanced by electrical stimulation. The stimulated, but not the spontaneous, release of the amine was Ca²⁺-dependent. Comparison with the release of newly taken up [³H]5-hydroxytryptamine showed that the specific radioactivity of electrically released 5-hydroxytryptamine was higher than that of either the spontaneously released or tissue amine. Stimulation also increased the release of 5-hydroxytryptamine more than that of its metabolites in the perfusate.These results indicate that 5-hydroxytryptamine is an endogeneous constituent of the enteric nervous system, that it is released by electrical field stimulation of enteric nerves, and that newly taken up 5-hydroxytryptamine is released preferentially by these neurons.