Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets.
BACKGROUND
Cerebral hypoxia/ischemia (HI) is not uncommon during the perinatal period. If occurring, it can result in severe neurologic disabilities that persist throughout life. Salvinorin A, a non-opioid Kappa opioid receptors (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. In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway.


RESULTS
The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitored before and 1 hour after HI in piglets equipped with a cranial window. Four groups of drug administration were performed after HI. The control group had DMSO (1 µl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 µg/kg, i.v.) administrated 0 and 30 min after HI, respectively. The 4(th) group had salvinorin A and the KOR antagonist norbinaltorphimine (Nor-BIN, 1 µM topical) co-administrated 0 min after HI (n = 5). The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorin A administration immediately or 30 min after HI. The preservation of autoregulation was abolished when nor-BIN was administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinal fluid (CSF) were measured before and 1 hour after HI. After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group. The elevated levels of pERK/ERK were not observed with salvinorin A only groups.


CONCLUSIONS
Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.
Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Zhenhong
Z
Wang
Nan
N
Ma
John
J
Riley
William M
WM
Armstead
Renyu
R
Liu
D061605:Administration, Intravenous; D000818:Animals; D000831:Animals, Newborn; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D045785:Diterpenes, Clerodane / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000134:cerebrospinal fluid; D006706:Homeostasis / Q000187:drug effects; D006935:Hypercapnia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D007022:Hypotension / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D034421:Sus scrofa; D014664:Vasodilation / Q000187:drug effects
D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; C090499:salvinorin A