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

Salvinorin A Administration After Global Cerebral Hypoxia/Ischemia Preserves Cerebrovascular Autoregulation via Kappa Opioid Receptor in Piglets

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Free PMC article

Salvinorin A Administration After Global Cerebral Hypoxia/Ischemia Preserves Cerebrovascular Autoregulation via Kappa Opioid Receptor in Piglets

Zhenhong Wang et al. PLoS One. .
Free PMC article

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effects of post HI salvinorin A administration on pial artery dilation to hypercapnia.
HI with DMSO impaired dilation of pial artery to hypercapnia. SA administrated at onset and 30 min after HI preserved the dilation of pial artery to moderate and severe hypercapnia, which were blunted by norbinaltorphimine (Norbin). N = 5 in each group. Percentage change =  (diameter after hypercapnia−diameter before hypercapnia)/diameter before hypercapnia)*100. SA: Salvinorin A; Moderate: hypercapnia with PaCO2 of 50 to 60 mmHg; Severe: hypercapnia with PaCO2 of 70 to 80 mmHg.
Figure 2
Figure 2. Effects of post HI salvinorin A administration on pial artery dilation to hypotension.
HI with DMSO damaged dilation of pial artery to hypotension. SA administrated at onset and 30 min after HI preserved the dilations of pial artery to moderate and severe hypotension, which were blunted by co-administration of norbinaltorphimine (Norbin). Percentage change =  (diameter after hypotension–diameter before hypotension)/diameter before hypotension)*100. N = 5 in each group. SA: Salvinorin A. Moderate: 25% decrease of mean blood pressure. Severe: 45% decrease of mean blood pressure.
Figure 3
Figure 3. Isoproterenol induced artery dilation was independent of KOR or ERK signaling.
Effects of isoproterenol (10 nM, 1 µM) on pial artery diameter before (baseline) and after HI did not change significantly in the presence and absence of various interventions, compared to baseline p>0.05. N = 5 in each group. Percentage change =  (diameter after isoproterenol−diameter before isoproterenol)/diameter before isoproterenol)*100; SA: Salvinorin A; Norbin: norbinaltorphimine.
Figure 4
Figure 4. Salvinorin A administration blocked the elevated CSF ERK activity observed 1 h after HI.
The ration of pERK/ERK at 1 hour after HI in the control groups (n = 10, DMSO and nor-BIN groups) increased significantly compared with the baseline. The baseline for all the groups are pulled together (n = 20) and the data from DMSO and nor-BIN groups were pulled together and presented as DMSO+Norbin (n = 10) to increase the power of the statistical analysis because of some large variances were observed. The elevated ERK activities were abolished in the groups with salvinorin A administrated immediately (n = 5) or 30 min (n = 5) after HI. Norbin: norbinaltorphimine; SA: Salvinorin A.

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