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First published online October 17, 2008
Journal of Experimental Biology 211, 3512-3517 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.021949

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-Opioid receptor antagonism induces NMDA receptor-dependent excitotoxicity in anoxic turtle cortex

Matthew E. Pamenter¹ and Leslie T. Buck^2,3,*

¹ Department of Pediatrics and Neuroscience, University of California San Diego, La Jolla, CA 92093, USA
² Department of Cellular and Systems Biology, University of Toronto, Toronto, ON, Canada, M5S 3G5
³ Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON, Canada, M5S 3G5

^* Author for correspondence (e-mail: buckl{at}zoo.utoronto.ca)

Accepted 15 September 2008

-Opioid receptor (DOR) activation is neuroprotective against short-term anoxic insults in the mammalian brain. This protection may be conferred by inhibition of N-methyl-D-aspartate receptors (NMDARs), whose over-activation during anoxia otherwise leads to a deleterious accumulation of cytosolic calcium ([Ca²⁺]_c), severe membrane potential (E_m) depolarization and excitotoxic cell death (ECD). Conversely, NMDAR activity is decreased by 50% with anoxia in the cortex of the painted turtle, and large elevations in [Ca²⁺]_c, severe E_m depolarization and ECD are avoided. DORs are expressed in high quantity throughout the turtle brain relative to the mammalian brain; however, the role of DORs in anoxic NMDAR regulation has not been investigated in turtles. We examined the effect of DOR blockade with naltrindole (1–10 µmol l^–1) on E_m, NMDAR activity and [Ca²⁺]_c homeostasis in turtle cortical neurons during normoxia and the transition to anoxia. Naltrindole potentiated normoxic NMDAR currents by 78±5% and increased [Ca²⁺]_c by 13±4%. Anoxic neurons treated with naltrindole were strongly depolarized, NMDAR currents were potentiated by 70±15%, and [Ca²⁺]_c increased 5-fold compared with anoxic controls. Following naltrindole washout, E_m remained depolarized and [Ca²⁺]_c became further elevated in all neurons. The naltrindole-mediated depolarization and increased [Ca²⁺]_c were prevented by NMDAR antagonism or by perfusion of the G_i protein agonist mastoparan-7, which also reversed the naltrindole-mediated potentiation of NMDAR currents. Together, these data suggest that DORs mediate NMDAR activity in a G_i-dependent manner and prevent deleterious NMDAR-mediated [Ca²⁺]_c influx during anoxic insults in the turtle cortex.

Key words: anoxic depolarization, channel arrest, excitotoxic cell death

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