Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 µg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala.

The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1 ) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here, we investigated the potential disruption of eCB/CB1 signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol. In the naïve rat BLA, the CB1 agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms. Notably, CB1 activation impaired ethanol's facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.

Predictive Value of ST-Segment Elevation in Lead aVR for Left Main and/or Three-Vessel Disease in Non-ST-Segment Elevation Myocardial Infarction.

BACKGROUND: ST-segment elevation in lead aVR predicts left main and/or three-vessel disease (LM/3VD) in patients with acute coronary syndromes. ST-segment elevation in lead aVR is generally reciprocal to and accompanied by ST-segment depression in precordial leads. Previous studies have assessed the independent predictive value of ST-segment elevation in lead aVR for LM/3VD in non-ST-segment elevation acute coronary syndrome and have reported conflicting results. METHODS: We performed a retrospective analysis of 379 patients with non-ST-segment elevation myocardial infarction (NSTEMI). Electrocardiograms on presentation were reviewed especially for ST-segment elevation ≥0.05 mV in lead aVR and ST-segment depression ≥0.05 mV in more than two contiguous leads in any other leads. RESULTS: Among 379 patients, 97 (26%) patients had ST-segment elevation in lead aVR and 88 (23%) patients had LM/3VD. Patients with ST-segment elevation in lead aVR had a higher rate of LM/3VD (39% vs. 18%; P < 0.001) and in-hospital revascularization (73% vs. 60%; P = 0.02) driven by a higher rate of in-hospital coronary artery bypass grafting (19% vs. 7%; P < 0.001) than those without ST-segment elevation in lead aVR. On multivariate analysis, ST-segment elevation in lead aVR (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.10-3.77; P = 0.02) and ST-segment depression in leads V1 -V4 (OR 2.99; 95% CI 1.46-6.15; P = 0.003) were independent predictors of LM/3VD. CONCLUSION: This study demonstrates that ST-segment elevation in lead aVR is an independent predictor of LM/3VD in patients with NSTEMI.

Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala.

The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and Type 1 cannabinoid receptor (CB1 ) expression and function in brain regions associated with addiction. CB1 inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naive rats, CB1 agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB1 antagonism, but not Type 2 cannabinoid receptor (CB2 ) antagonism. After 2-3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB1 function. The CB1 antagonist AM251 revealed a tonic eCB/CB1 control of GABAergic transmission in the alcohol-naive CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB1 influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naive and ethanol-exposed rats. Although CB1 activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB1 signaling in the ethanol effect. Collectively, these observations demonstrate an important CB1 influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB1 signaling.

Absence of ST-segment elevation in lead V1 predicts worse long-term outcomes in patients with first anterior ST-segment elevation myocardial infarction.

BACKGROUND: The prognostic value of ST-segment elevation in lead V1 (STE in V1) in anterior ST-segment elevation myocardial infarction (STEMI) has not been elucidated. METHODS: We performed a retrospective analysis of 190 consecutive first anterior STEMI patients. STE in V1 ≥0.1mV was recorded. Major adverse cardiac events (MACE) were defined as a composite of all-cause death, recurrent myocardial infarction, or target vessel revascularization. RESULTS: Among 190 patients, 42 patients did not have STE in V1. The patient without STE in V1 had a higher peak creatine kinase value and a higher incidence of 1-year MACE (36% vs. 13%, p<0.001), driven by a higher mortality (24% vs. 5%, p<0.001). The absence of STE in V1 was an independent predictor for 1-year MACE (odds ratio 3.16; 95% confidence interval 1.28-7.83; p=0.01). CONCLUSION: The absence of STE in V1 was an independent predictor for worse long-term outcomes in patients with first anterior STEMI.

Tpeak - Tend and Tpeak - Tend /QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients.

BACKGROUND: Cardiac resynchronization therapy (CRT) increases transmural dispersion of repolarization (TDR) and can be pro-arrhythmic. However, overall arrhythmia risk was not increased in large-scale CRT clinical trials. Increased TDR as measured by T(peak ) -T(end) (TpTe) was associated with arrhythmia risk in CRT in a single-center study. This study investigates whether QT interval, TpTe, and TpTe/QT ratio are associated with ventricular arrhythmias in patients with CRT-defibrillator (CRT-D). METHODS: Post-CRT-D implant electrocardiograms of 128 patients (age 71.3 years ± 10.3) with at least 2 months of follow-up at our institution's device clinic (mean follow-up of 28.5 months ± 17) were analyzed for QT interval, TpTe, and TpTe/QT ratio. Incidence of ventricular arrhythmias was determined based on routine and directed device interrogations. RESULTS: Appropriate implantable cardioverter-defibrillator therapy for sustained ventricular tachycardia or ventricular fibrillation was delivered in 18 patients (14%), and nonsustained ventricular tachycardia (NSVT) was detected but did not require therapy in 58 patients (45%). Patients who received appropriate defibrillator therapy had increased TpTe/QT ratio (0.24 ± 0.03 ms vs 0.20 ± 0.04, P = 0.0002) and increased TpTe (105.56 ± 20.36 vs 87.82 ± 22.32 ms, P = 0.002), and patients with NSVT had increased TpTe/QT ratio (0.22 ± 0.04 vs 0.20 ± 0.04, P = 0.016). Increased QT interval was not associated with risk of ventricular arrhythmia. The relative risk for appropriate defibrillator therapy of T(p) T(e) /QT ratio ≥ 0.25 was 3.24 (P = 0.016). CONCLUSION: Increased TpTe and increased TpTe/QT ratio are associated with increased incidence of ventricular arrhythmias in CRT-D. The utility of TpTe interval and TpTe/QT ratio as potentially modifiable risk factors for ventricular arrhythmias in CRT requires further study.

The prognostic significance of frequency and morphology of premature ventricular complexes during ambulatory holter monitoring.

BACKGROUND: Multiform premature ventricular complexes (PVCs) are associated with an adverse prognosis in patients with structural heart disease. Very frequent PVCs are associated with ventricular dysfunction. Our hypothesis is that multiform PVCs confer an adverse prognosis in the general population. METHODS: We performed a retrospective cohort study of patients ≥18 years old referred to our institution for 24-hour ambulatory Holter monitoring between July 1, 2008 and December 31, 2009. Holters without PVCs or with more frequent ectopy (couplets, triplets, or nonsustained ventricular tachycardia) were excluded. Clinical and adverse event (AE) data ("major adverse cardiovascular event" or new/worsening heart failure) were gathered from chart review. Data was analyzed by PVC frequency (rare, occasional, or frequent) and pattern (uniform or multiform). RESULTS: A total of 222 patients (43% male, mean age: 55 ± 16 years) were evaluated (median follow-up 2.3 years [IQR: 2.0-2.6]). Median frequency was 2 PVCs per hour (IQR: 1-13). Multiform PVCs were noted in 48%. Patients with multiform PVCs were older, and had a higher prevalence of comorbidities. Thirty-nine AE were noted. Patients with an AE were younger, had a higher prevalence of HTN, diabetes, CAD, CHF, and previous MI. The multiform group had a higher incidence of AE (28%) compared to the uniform group (8%) (P < 0.001). Increasing PVC frequency was associated with a higher incidence of AE (8% vs 24% vs 35%, respectively). In Cox regression analyses, the multiform pattern but not frequency predicted AE. CONCLUSIONS: Multiform PVCs were associated with a 4-fold increase in AE in patients referred for ambulatory Holter monitoring.

Prognostic impact of terminal T wave inversions on presentation in patients with ST-elevation myocardial infarction undergoing urgent percutaneous coronary intervention.

INTRODUCTION: Terminal T wave inversions (TTWI) indicate advanced stages of ST-elevation myocardial infarction (STEMI). The present study investigated whether TTWI predict unfavorable in-hospital outcomes in STEMI patients treated with urgent percutaneous coronary intervention (PCI). METHODS: A retrospective cohort study was performed with consecutive 188 STEMI cases undergoing urgent PCI. The primary endpoint was in-hospital major adverse cardiac event (MACE), and the secondary endpoints were ST resolution (STR) after PCI and length of stay (LOS). RESULTS: TTWI on presentation were independently associated with higher incidence of in-hospital MACE (adjusted OR 2.8; 95% CI 1.1-7.0; p=0.03), inadequate STR (adjusted OR 5.5; 95% CI 2.1-14.3; p=0.01), and longer LOS (adjusted mean increase 4.1 days; 95% CI 0.3-7.9; p=0.03). TTWI predicted these outcomes better than patient-reported ischemic time or pathologic Q waves. CONCLUSIONS: TTWI on presentation are an independent risk factor for poor inpatient prognosis among patients presenting with STEMI undergoing urgent PCI.

The effect of statin therapy on ventricular tachyarrhythmias: a meta-analysis.

The objective of this study was to assess whether statin therapy is associated with a reduction in ventricular tachyarrhythmias. Statins have been shown to be beneficial beyond their cholesterol-lowering effects. These pleiotropic effects have been implicated in the protection against atrial fibrillation and the reduction in appropriate implantable cardioverter-defibrillator therapy in patients with coronary artery disease. This meta-analysis was conducted to evaluate whether statins were associated with a reduction in ventricular tachyarrhythmias in patients with coronary artery disease or nonischemic cardiomyopathy. The Medline and Cochrane databases were searched for studies in human subjects published in the English language between 1985 and February 2010. Studies were included in our analysis if they provided data regarding the association between the use of statins and the incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with coronary artery disease or nonischemic cardiomyopathy. The occurrence of ventricular arrhythmias was defined as the VT/VF occurrence or appropriate implantable cardioverter-defibrillator therapy for VT/VF. Of the 166 identified articles, nine prospective studies with 150,953 patients enrolled met our inclusion criteria and were included in this analysis. Using a random effects model, statin therapy was associated with a 31% reduction in the risk of VT/VF when compared with the group not on statin therapy (pooled relative risk = 0.69, 95% confidence interval, 0.58-0.83; heterogeneity I² = 57.3%). There was a low likelihood of publication bias in this analysis (Egger's test P = 0.957). Statin use in patients with coronary artery disease or nonischemic cardiomyopathy is associated with a 31% reduction in the development of ventricular tachyarrhythmias.

Electrocardiographic predictors of culprit artery in acute inferior ST elevation myocardial infarction.

BACKGROUND: In acute inferior ST-segment elevation myocardial infarction (STEMI), multiple electrocardiographic algorithms have been proposed to predict the culprit artery. Our purpose is to review these and compare them to ST depression in lead aVR to predict culprit artery in inferior STEMI. METHODS: In 106 patients with acute inferior STEMI who underwent emergent coronary angiography, we correlated electrocardiographic and angiographic findings pertaining to the culprit artery. We then reviewed the algorithms proposed by Fiol et al and Tierala et al, and applied them and our own from Kanei et al using ST depression in aVR for predicting the left circumflex artery (LCx) as the culprit, to the population. Finally, we compared the sensitivities and specificities of the respective algorithms for predicting the culprit artery. RESULTS: The sensitivity and specificity of ST depression in lead aVR to predict LCx as the culprit were 53% and 86%, respectively, and 86% and 55%, respectively for predicting the right coronary artery (RCA) as the culprit. When their algorithms were applied to our population, the sensitivities and specificities of Fiol et al and Tierala et al were slightly higher. CONCLUSION: Compared to other proposed algorithms, ST depression in aVR is a simple method with satisfactory sensitivity and specificity to predict the culprit artery in inferior STEMI.

Warfarin in haemodialysis patients with atrial fibrillation: what benefit?

Warfarin is commonly used to prevent stroke in patients with atrial fibrillation; however, patients on haemodialysis may not derive the same benefit from warfarin as the general population. There are no randomized controlled studies in dialysis patients which demonstrate the efficacy of warfarin in preventing stroke. In fact, warfarin places the dialysis patient at increased risk for haemorrhagic stroke and possibly ischaemic stroke. Additionally, warfarin increases the risk of major bleeding and has been associated with vascular calcification. Routine use of warfarin in dialysis for stroke prevention should be discouraged, and therapy should only be reserved for dialysis patients at high risk for thrombo-embolic stroke and carefully monitored if implemented.

ST-segment depression in aVR as a predictor of culprit artery and infarct size in acute inferior wall ST-segment elevation myocardial infarction.

BACKGROUND: ST-segment depression in lead aVR in acute inferior wall ST-segment elevation myocardial infarction (STEMI) has recently been suggested as a predictor of left circumflex (LCx) artery involvement. The purpose of this study is to evaluate the clinical significance of aVR depression during inferior wall STEMI. METHODS: This study included 106 consecutive patients who presented with inferior wall STEMI and underwent urgent coronary angiogram. Clinical and angiographic findings were compared between patients with and without aVR depression > or = 0.1 mV. RESULTS: The sensitivity and specificity of aVR depression as a predictor of LCx infarction were 53% and 86%, respectively. In patients with right coronary artery infarction, aVR depression was associated with increased cardiac enzymes and the involvement of a large posterolateral branch, which may explain the larger infarction. CONCLUSIONS: ST-segment depression in lead aVR in inferior wall STEMI predicts LCx infarction or larger RCA infarction involving a large posterolateral branch.

Differential alteration of hippocampal excitatory synaptic transmission by cannabinoid ligands.

Cannabinoid compounds affect synaptic activity and plasticity in numerous brain areas by activating CB1 receptors (CB1). In hippocampus, varying results have been obtained on the extent and site of cannabinoid actions on excitatory transmission, ranging from no effect to complete obliteration of synaptic responses. Here we used the rat hippocampal slice preparation to study and compare the effect of various synthetic and endogenous CB1 ligands on excitatory synaptic transmission. The full CB1 agonist WIN55212-2 (WIN2) greatly decreased excitatory synaptic transmission by 62%. The effect of WIN-2 was concentration dependent (EC50 of 200 nM) and completely prevented by CB1 antagonists. The nondegradable partial CB1 agonist R1-methanandamide (mAEA) decreased transmission by 25% and the endocannabinoids 2-arachidonylglycerol (2-AG) and anandamide (AEA) had no significant effect. The action of AEA was improved by inhibiting its degradation but not its transport. The effect of 2-AG was enhanced upon inhibition of COX-2 but remained unchanged with blockade of monoacylglycerol lipase (MAGL). The observed effects were prevented by CB1 antagonists regardless of the ligand used, and paired-pulse paradigms pointed to presynaptic mechanisms of cannabinoid action. Our results show that cannabinoid effects on neuronal activity differ widely according to the CB1 ligand used. We observed large differences between full (synthetic) and partial (endogenous) CB1 agonists in altering synaptic transmission, notably because of the involvement of active degradation mechanisms.

Termination of recurrent ventricular tachycardia by continuous positive airway pressure ventilation.

We report a case of hypertrophic cardiomyopathy with recurrent ventricular tachycardia that resolved after initiating continuous positive airway pressure therapy.

Atrial rate and rhythm abnormalities in a patient with hyperkalemia.

A 67 year old man presented with a serum potassium of 7.7 mEq/L and slow atrial flutter with variable A-V block and peaked T waves. Initial treatment for hyperkalemia was followed by an increase in the atrial flutter rate to 300 beats per minute. After hemodialysis the rhythm converted to sinus.

Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats.

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.

Successful transition to buprenorphine in a patient with methadone-induced torsades de pointes.

A 56-year-old-man presented with syncope and torsades de pointes secondary to methadone-induced QT prolongation. After transition from methadone to buprenorphine, a partial mu-opiate-receptor agonist and a kappa-opiate-receptor antagonist, the QT normalized and ventricular arrhythmias resolved. Buprenorphine should be used for opiate dependence and chronic pain in patients with methadone-induced QT prolongation and as first line therapy in patients with risk factors for torsades de pointes.

Dynorphin Counteracts Orexin in the Paraventricular Nucleus of the Thalamus: Cellular and Behavioral Evidence.

The orexin (Orx) system plays a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orx and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Previous studies suggested that OrxA transmission in the posterior paraventricular nucleus of the thalamus (pPVT) participates in cocaine-seeking behavior. This study determined whether Orx and Dyn interact in the pPVT. Using the brain slice preparation for cellular recordings, superfusion of DynA onto pPVT neurons decreased the frequency of spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs). OrxA increased the frequency of sEPSCs but had no effect on mEPSCs, suggesting a network-driven effect of OrxA. The amplitudes of s/mEPSCs were unaffected by the peptides, indicating a presynaptic action on glutamate release. Augmentation of OrxA-induced glutamate release was reversed by DynA. Utilizing a behavioral approach, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After extinction, rats received intra-pPVT administration of OrxA±DynA±the κ-opioid receptor antagonist nor-binaltorphimine (NorBNI) under extinction conditions. OrxA reinstated cocaine- and SCM-seeking behavior, with a greater effect in cocaine animals. DynA blocked OrxA-induced cocaine seeking but not SCM seeking. NorBNI did not induce or potentiate cocaine-seeking behavior induced by OrxA but reversed DynA effect. This indicates that the κ-opioid system in the pPVT counteracts OrxA-induced cocaine seeking, suggesting a novel therapeutic target to prevent cocaine relapse.

CRF modulates glutamate transmission in the central amygdala of naïve and ethanol-dependent rats.

Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) is hypothesized to drive the development of alcohol dependence, as it regulates ethanol intake and several anxiogenic behaviors linked to withdrawal. Excitatory glutamatergic neurotransmission contributes to alcohol reinforcement, tolerance and dependence. Therefore, in this study we used in vitro slice electrophysiology to investigate the effects of CRF and its receptor subtype (CRF1 and CRF2) antagonists on both evoked and spontaneous action potential-independent glutamatergic transmission in the CeA of naive and ethanol-dependent Sprague-Dawley rats. We found that CRF (25-200 nM) concentration-dependently diminished evoked compound excitatory postsynaptic potentials (EPSPs), but increased miniature excitatory postsynaptic current (mEPSC) frequencies similarly in CeA neurons of both naïve and ethanol-dependent rats, indicating reduced evoked glutamatergic responses and enhanced vesicular glutamate release, respectively. This CRF-induced vesicular glutamate release was prevented by the CRF1/2 antagonist (Astressin B) and the CRF1 antagonist (R121919), but not by the CRF2 antagonist (Astressin 2B). Similarly, CRF's effects on evoked glutamatergic responses were completely blocked by CRF1 antagonism, but only slightly decreased in the presence of the CRF2 antagonist. Moreover, CRF1 antagonism reveals a tonic facilitation of vesicular glutamate, whereas the CRF2 antagonism revealed a tonic inhibition of vesicular glutamate release. Collectively our data show that CRF primarily acts at presynaptic CRF1 to produce opposite effects on CeA evoked and spontaneous glutamate release and that the CRF system modulates CeA glutamatergic synapses throughout the development of alcohol dependence.