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

Wang Z, Ma N, Riley J, Armstead WM, Liu R - PLoS ONE (2012)

Bottom Line: If occurring, it can result in severe neurologic disabilities that persist throughout life.After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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 ยตl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 ยตg/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 ยตM topical) co-administrated 0 min after HI (nโ€Š=โ€Š5). 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.

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Related in: MedlinePlus

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 (nโ€Š=โ€Š10, DMSO and nor-BIN groups) increased significantly compared with the baseline. The baseline for all the groups are pulled together (nโ€Š=โ€Š20) and the data from DMSO and nor-BIN groups were pulled together and presented as DMSO+Norbin (nโ€Š=โ€Š10) 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 (nโ€Š=โ€Š5) or 30 min (nโ€Š=โ€Š5) after HI. Norbin: norbinaltorphimine; SA: Salvinorin A.
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pone-0041724-g004: 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 (nโ€Š=โ€Š10, DMSO and nor-BIN groups) increased significantly compared with the baseline. The baseline for all the groups are pulled together (nโ€Š=โ€Š20) and the data from DMSO and nor-BIN groups were pulled together and presented as DMSO+Norbin (nโ€Š=โ€Š10) 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 (nโ€Š=โ€Š5) or 30 min (nโ€Š=โ€Š5) after HI. Norbin: norbinaltorphimine; SA: Salvinorin A.

Mentions: The ERK activities are quantified as the ratio of pERK/ERK levels in CSF. The ERK activity data in groups without salvinorin effects (DMSO group and SA+Norbin group; renamed as DMSO+Nornin group) are combined. As indicated in figure 4, the ERK activity in groups without salvinorin increased significantly 60 min after HI (p<0.05 as compared with pre-HI baseline). The ERK activity of salvinorin A administration groups reduced to the baseline level.


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

Wang Z, Ma N, Riley J, Armstead WM, Liu R - PLoS ONE (2012)

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 (nโ€Š=โ€Š10, DMSO and nor-BIN groups) increased significantly compared with the baseline. The baseline for all the groups are pulled together (nโ€Š=โ€Š20) and the data from DMSO and nor-BIN groups were pulled together and presented as DMSO+Norbin (nโ€Š=โ€Š10) 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 (nโ€Š=โ€Š5) or 30 min (nโ€Š=โ€Š5) after HI. Norbin: norbinaltorphimine; SA: Salvinorin A.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3404042&req=5

pone-0041724-g004: 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 (nโ€Š=โ€Š10, DMSO and nor-BIN groups) increased significantly compared with the baseline. The baseline for all the groups are pulled together (nโ€Š=โ€Š20) and the data from DMSO and nor-BIN groups were pulled together and presented as DMSO+Norbin (nโ€Š=โ€Š10) 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 (nโ€Š=โ€Š5) or 30 min (nโ€Š=โ€Š5) after HI. Norbin: norbinaltorphimine; SA: Salvinorin A.
Mentions: The ERK activities are quantified as the ratio of pERK/ERK levels in CSF. The ERK activity data in groups without salvinorin effects (DMSO group and SA+Norbin group; renamed as DMSO+Nornin group) are combined. As indicated in figure 4, the ERK activity in groups without salvinorin increased significantly 60 min after HI (p<0.05 as compared with pre-HI baseline). The ERK activity of salvinorin A administration groups reduced to the baseline level.

Bottom Line: If occurring, it can result in severe neurologic disabilities that persist throughout life.After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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 ยตl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 ยตg/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 ยตM topical) co-administrated 0 min after HI (nโ€Š=โ€Š5). 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.

Show MeSH
Related in: MedlinePlus