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BJA Advance Access originally published online on August 17, 2007
British Journal of Anaesthesia 2007 99(4):538-546; doi:10.1093/bja/aem220
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effects of delta-opioid receptor stimulation and inhibition on hippocampal survival in a rat model of forebrain ischaemia

M. Iwata1, S. Inoue1,*, M. Kawaguchi1, M. Nakamura2, N. Konishi2 and H. Furuya1

1 Department of Anesthesiology
2 Department of Pathology, Nara Medical University, 840 Shijo-cho Kashihara, Nara 634-8522, Japan

* Corresponding author. E-mail: seninoue{at}naramed-u.ac.jp

Background: It has been reported that delta-opioid (DOP) receptor agonists may be neuroprotective in the central nervous system. However, the DOP agonist [D-Ala2, D-Leu5]enkephalin (DADLE) does not produce neuroprotection in severe forebrain ischaemia. The aim of this study was to examine the effects of DADLE on hippocampal neurone survival against less severe forebrain ischaemia.

Methods: Intraperitoneal injection of DADLE (0 or16 mg kg–1) in male Sprague–Dawley rats was performed 30 min before ischaemia. Severe (10 min), moderate (8 min), or mild (6 min) forebrain ischaemia was produced by bilateral carotid occlusion combined with hypotension (35 mm Hg) under isoflurane (1.5%) anaesthesia. Naltrindole (10 mg kg–1) (DOP antagonist) was administered 30 min before DADLE in order to confirm DOP receptor activation in the neuroprotective efficacy of DADLE. Naltrindole alone was also administered 30 min before ischaemia to examine endogenous DOP agonism as a self-protecting mechanism against ischaemia. All animals were evaluated neurologically and histologically after a 1 week recovery period.

Results: DADLE improved neurone survival in hippocampal CA3 and dentate gyrus (DG) sectors. CA1 neurones were not protected against moderate and mild ischaemia. Naltrindole abolished DADLE neuroprotection in the CA3 and DG after both moderate and mild ischaemia. Interestingly, regardless of co-administration of DADLE, naltrindole significantly worsened neuronal injury in the CA1 region after mild ischaemia.

Conculsions: These results suggest that DADLE provides limited neuroprotection to relatively ischaemia-resistant regions but not to selectively vulnerable regions. This was probably mediated by DOP stimulation. Pre-ischaemic treatment with a DOP antagonist, regardless of co-administration of DADLE, worsened neuronal damage at the selectively vulnerable regions only after mild forebrain ischaemia. These data suggest that DOP activation with endogenous DOP ligand may be involved in self-protecting ischaemia-sensitive regions of the brain.

Keywords: analgesics opioid, DADLE; analgesics opioid, delta-opioid; antagonists opioid, nattrindole; brain, hippocampus, neuroprotection; brain, ischaemis, forebrain ischaemia


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