Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets

PLoS One. 2012;7(7):e41724. doi: 10.1371/journal.pone.0041724. Epub 2012 Jul 24.


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.

Methodology/principal findings: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Animals, Newborn
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / enzymology
  • Cerebral Arteries / pathology
  • Cerebral Arteries / physiopathology
  • Cerebrovascular Circulation* / drug effects
  • Diterpenes, Clerodane / administration & dosage*
  • Diterpenes, Clerodane / pharmacology
  • Diterpenes, Clerodane / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / cerebrospinal fluid
  • Homeostasis* / drug effects
  • Hypercapnia / complications
  • Hypercapnia / pathology
  • Hypercapnia / physiopathology
  • Hypotension / complications
  • Hypotension / drug therapy
  • Hypotension / pathology
  • Hypotension / physiopathology
  • Hypoxia-Ischemia, Brain / complications
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / physiopathology*
  • Isoproterenol / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Pia Mater / blood supply
  • Pia Mater / drug effects
  • Pia Mater / physiopathology
  • Receptors, Opioid, kappa / metabolism*
  • Sus scrofa
  • Vasodilation / drug effects


  • Diterpenes, Clerodane
  • Receptors, Opioid, kappa
  • Extracellular Signal-Regulated MAP Kinases
  • Isoproterenol
  • salvinorin A