Salvinorin A Administration after Global Cerebral HypoxiaIschemia Preserves Cerebrovascular Autoregulation via Kappa Opioid Receptor in Piglets 英文参考文献.docVIP

SalvinorinAAdministrationafterGlobalCerebral Hypoxia/IschemiaPreservesCerebrovascular AutoregulationviaKappaOpioidReceptorinPiglets ZhenhongWang1,2,NanMa1,JohnRiley1,WilliamM.Armstead1*,RenyuLiu1* 1Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 2Department of Anesthesiology,SchoolofMedicine,RenjiHospital,ShanghaiJiaotongUniversity,Shanghai,China Abstract Background: Cerebral hypoxia/ischemia (HI) is not uncommon during the perinatal period. If occurring, it can result in severeneurologicdisabilitiesthatpersistthroughoutlife.SalvinorinA,anon-opioidKappaopioidreceptors(KOR)selective agonist, has the potential to address this devastating situation. We have demonstrated that salvinorin A administration before HI, preserves pial artery autoregulative function through both the KOR and extracellular signal-regulated kinases (ERK)pathways.Inthepresentstudy,wetestedthehypothesisthatadministrationofsalvinorinAafterHIcouldpreserve cerebralautoregulationviaKORandERKpathway. Methodology/Principal Findings: The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitoredbeforeand1hourafterHIinpigletsequippedwithacranialwindow.Fourgroupsofdrugadministrationwere performedafterHI.ThecontrolgrouphadDMSO(1ml/kg,i.v.)administratedimmediatelyafterHI.TwosalvinorinAtreated groupshadsalvinorinA(10mg/kg,i.v.)administrated0and30minafterHI,respectively.The4 grouphadsalvinorinAand the KOR antagonist norbinaltorphimine (Nor-BIN, 1mM topical) co-administrated 0min after HI (n=5). The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorinAadministrationimmediatelyor30minafterHI.Thepreservationofautoregulationwasabolishedwhennor-BIN was administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinal fluid (CSF) were measured before and 1hour afterHI.AfterHI,thepERK/ERKlevelssignificantl