SB-334867-A antagonises orexin mediated excitation in the locus coeruleus

Original article can be found at: http://www.sciencedirect.com/science/journal/00283908 Copyright Elsevier Ltd. [Full text of this article is not available in the UHRA]Electrophysiological recordings from identified noradrenergic locus coeruleus (LC) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can triple the firing rate of spontaneously active LC neurones, quantitative pharmacological analysis that determines the receptor subtype(s) mediating the orexinergic response has not yet been performed. Here we demonstrate that the effects of orexin-A are five-fold more potent than orexin-B on LC neuronal excitability. We show further that the orexin receptor antagonist SB-334867-A inhibits the effects of both agonists with pKB values similar to those calculated for human OX1 receptors expressed in CHO cells. Finally, we found no evidence for tonic activation of OX1 receptors in LC noradrenergic neurones despite electron microscopic evidence that orexin terminals directly contact these neurones. These data demonstrate that SB-334867-A is a useful tool compound with which to study the physiology of OX1 receptors.Peer reviewe

Anaesthetic care of patients undergoing primary hip and knee arthroplasty: consensus recommendations from the International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) based on a systematic review and meta-analysis

Background: Evidence-based international expert consensus regarding anaesthetic practice in hip/knee arthroplasty surgery is needed for improved healthcare outcomes. Methods: The International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) systematic review, including randomised controlled and observational studies comparing neuraxial to general anaesthesia regarding major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, genitourinary, thromboembolic, neurological, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, from 1946 to May 17, 2018 were queried. Meta-analysis and Grading of Recommendations Assessment, Development and Evaluation approach was utilised to assess evidence quality and to develop recommendations. Results: The analysis of 94 studies revealed that neuraxial anaesthesia was associated with lower odds or no difference in virtually all reported complications, except for urinary retention. Excerpt of complications for neuraxial vs general anaesthesia in hip/knee arthroplasty, respectively: mortality odds ratio (OR): 0.67, 95% confidence interval (CI): 0.57–0.80/OR: 0.83, 95% CI: 0.60–1.15; pulmonary OR: 0.65, 95% CI: 0.52–0.80/OR: 0.69, 95% CI: 0.58–0.81; acute renal failure OR: 0.69, 95% CI: 0.59–0.81/OR: 0.73, 95% CI: 0.65–0.82; deep venous thrombosis OR: 0.52, 95% CI: 0.42–0.65/OR: 0.77, 95% CI: 0.64–0.93; infections OR: 0.73, 95% CI: 0.67–0.79/OR: 0.80, 95% CI: 0.76–0.85; and blood transfusion OR: 0.85, 95% CI: 0.82–0.89/OR: 0.84, 95% CI: 0.82–0.87. Conclusions: Recommendation: primary neuraxial anaesthesia is preferred for knee arthroplasty, given several positive postoperative outcome benefits; evidence level: low, weak recommendation. Recommendation: neuraxial anaesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation. Based on current evidence, the consensus group recommends neuraxial over general anaesthesia for hip/knee arthroplasty. Trial registry number: PROSPERO CRD42018099935. © 2019 British Journal of Anaesthesi

Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain.

An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via redundancy', wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wake-promoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm's law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin ➔ histamine ➔ noradrenaline/serotonin-orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops