¹Department of Pediatrics, Section of Respiratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence: Dr Y Xia, Yale, Department of Pediatrics, University School of Medicine, 333 Cedar Street, LMP 3107, New Haven, CT 06520, USA. E-mail: ying.xia@yale.edu

Received 7 March 2006; Revised 4 May 2006; Accepted 11 May 2006; Published online 14 June 2006.

Abstract

Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that -opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K⁺, which plays a role in neuronal death, we asked whether DOR activation preserves K⁺ homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K⁺-sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen–glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala², D-Leu⁵]-enkephalinamide attenuated the anoxia- and OGD-induced increase in extracellular K⁺ and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K⁺ and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K⁺ homeostasis. These data suggest that activation of DOR protects the cortex against anoxia- or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K⁺ homeostasis during anoxia or ischemia.