Aging-related Orexin Changes Are Involved In The Delayed Emergence From General Anesthesia And The Role Of Histaminergic System In Orexin Induced Anesthesia-arousal Regulation

Background: Delayed emergence from general anesthesia frequently occurs inelderly patients, but the reason is not clear. orexin has been shown to be invovled inarousal from general anesthesia. The aim of this study was to find the reason that elderlyanimals need more time to wake from inhaled anesthesia by examining orexin and its receptors expression in both elderly and young animals.Methods: We recruited41patients scheduled for elective lumbar surgery andevaluated34patients. Patients were divided into a young group (age30-55, n=16) and anelderly group (age65-77, n=18). Anesthesia with sevoflurane-remifentanil was titrated tomaintain the bispectral index between45and65. The times from stopping anesthesia toeyes opening and extubation were recorded. Arterial blood was collected, and plasmaorexin-A was determined by radioimmunoassay at the following four time points:pre-anesthesia (T0),1h following anesthesia induction (T1), emergence (5min afterextubation)(T2), and30min after extubation (T3).Results: The times from stopping anesthesia to eyes opening and extubation wereboth significantly longer in the elderly group than in the young group (P=0.004, P=0.01,respectively). Basal (T0) orexin-A levels were higher in the elderly group than in theyoung group (T0,26.13±1.25vs17.9±1.30pg/ml, P<0.0001). Induction of anesthesia didnot change plasma orexin-A levels in either group, but they significantly increased in boththe young (29.2±1.9pg/ml) and elderly (35.0±1.7pg/ml) groups from T0to T2(P<0.0001,both). Orexin-A levels were significantly higher in the elderly than in the young group atT1, T2and T3.Conclusion: Plasma orexin may not be responsible for delayed emergence fromisoflurane anesthesia of elderly. Background: Histaminergic system plays an important role in keeping clear. Studieshave shown that it is involved in the process of orexin regulation of general anesthesia, butwhich subtype of orexin regulated and by which subtypes of histamine receptors remains not clearly. The aim of this study was to find which subtypes recepors of orexin inTuberomammillary Nucleus (TMN) can facilitae awakening from isoflurane throughhistamine receptors and further to demonstrate the real subtypes of histamine involved inthis process.Methods: Adult male SD rats (body weight230-280g) were anesthetized by10%chloral hydrate (1ml/kg, ip) to do the following work.1) Guide cannulas formicroinjection to the TMN and4stainless screws for monitoring EEG were embedded.Seven days later, we injected orexin-A (100pmol/0.3μL) and its antagonist SB334867(20μg/0.3μL) to observe the induction time, awakening time and EEG in rats.2) The sameoperation as step1, Seven days later, we injected orexin-B (100pmol/0.3μL) and itsantagonist TCS-OX2-29(20μg/0.3μL) to observe the time of induction, awakening andEEG in rats.3) Guide cannulas for microinjection to lateral ventricle and TMN and4stainless screw for EEG were embedded. We injected antagonist of histamine receptor1triprolidine (totally25μg/1μL) to lateral ventricle and orexin-A (or orexin-B,100pmol/0.3μL) to TMN7d later to observe the induction time, awakening time and EEG inrats.4) The same operation as step3, histamine receptor antagonists cimetidine (25μg/1μL)and orexin-A (or orexin-B,100pmol/0.3μL)were respectively injected to lateral ventricleand TMN7days later, then we watched the same target as step1.The induction time wasdefined as the time of righting reflex disappeared. The awakening time defined as thattime of righting reflex regained. Before the anesthesia of four steps, we put rats in acontainer which was filled with isoflurane (1MAC,1.4%) and recorded the induction time,awakening time and EEG.5)30minutes before anesthesia, we injected triprolidine(25μg/1μL) and cimetidine (25μg/1μL) to lateral ventricle.15minutes before anesthesia,orexin-A was injected to TMN. During anesthesia, rats were placed in a sealed container,then the oxygen flow rate was1L/min, the inhaled concentration is set to5%, theinduction time and emergence time were recorded.Results:(1) Conventional-induced rats in each group, the induction time was notdifferent statistically.(2)The rats which injected orexin-A (100pmol/0.3μL) awaked muchfaster than controled group (injected saline0.3μL)（16.19±0.87min vs24.17±3.22min， P<0.05），there was no significant difference between the rats received orexin-B andcontrol rats which awakening time was20.17±1.62min vs24.17±3.22min，P>0.05.(3)The injection of OX1R antagonist SB334867(20μg/0.3μL) to TMN could prolong theawakening time compared to the solvent DMSO (0.3μL) group.The time was respectively34.96±1.51min vs26.60±2.37min, P<0.05.The injection of OX2R antagonistTCS-OX2-29did not significantly affect the rat awakening time (24.47±2.07min vs26.60±2.37min, P>0.05).(4) Microinjection of histamine receptor1antagonisttriprolidine to the lateral ventricle did not infect the shorter awakening time caused byorexin-A (H1Ra+OX-A vs saline+OX-A:16.98±2.08min vs15.83±0.56min, P>0.05), but injection orexin-B could reverse this effect.(H2RA+OX-A vs saline+OX-A:22.60±2.30min vs15.83±0.56min, P<0.05). Compared with the control group, therewas no significant difference (H2RA+OX-A vs saline+saline:22.60±2.30min vs23.83±1.34min, P>0.05).(5) gradually induced results showed that: compared with thecontrol group, the TMN nucleus microinjection OX-A significantly delayed the inductiontime (saline+OX-A vs saline+saline:3.20±0.07min vs4.90±0.07min, P<0.05),intracerebroventricular microinjection histamine H1receptor antagonist triprolidine(25μg/1μL)(H1Ra+OX-A:4.90±0.20min) did not show similar results.(P>0.05nosignificant difference), but the H2receptor antagonist cimetidine (25μg/1μL)intracerebroventricular injection (H2Ra+OX-A:3.15±0.05) reversed the extension ofinduction time caused by ox-A compared with the control group.Conclusion: In the TMN of rat hypothalamus, orexin-A could promote awakeningand delay the induction, mainly through by histamine receptor2.