Glutamatergic effects of dynorphin peptides on cultured oligodendrocytes

Abstract

Our previous work has shown that oligodendrocytes (OLs), in addition to neurons, can synthesize the endogenous opioid dynorphin A (dyn A). Opioid effects of dynorphin are preferentially mediated through kappa opioid receptors (KORs). Signalling through KORs appears to promote OL survival in culture since blockade of KORs with the specific antagonist nor‐binaltorphamine significantly reduces OL survival and exacerbates glutamate toxicity. Structure‐activity studies have shown that kappa ligand activity resides in the N‐terminus of dyn A derived‐peptides, while C‐terminal fragments exhibit glutamatergic effects on neurons through NMDA and/or AMPA/kainate receptors. The present study was undertaken to determine whether dynorphin peptides also have glutamatergic effects on OLs. Since OLs grown in vitro are thought to have an AMPA/kainate phenotype, OLs were treated with dyn A (1–17) or dyn A (2–17) in the presence or absence of CNQX. Survival of mature and immature OLs was assessed over 72 h using a sensitive repeated measures assay. Dyn A (1–17) had no effect on OL survival. Dyn A (2–17), a dyn A‐derived peptide with nominal opioid activity, significantly reduced the survival of both immature and mature OLs. The effect was completely reversible in mature OLs by addition of CNQX at 2 h prior to dyn A (2–17), but not by simultaneous addition of CNQX. Of great interest, CNQX was unable to reverse the toxicity of dyn A (2–17) on immature OLs, suggesting that dynorphin toxicity in this population is mediated via an alternate glutamate receptor type. CNQX alone had no effect on OL viability. Results suggest that elevated dynorphin levels in CNS disease and trauma may contribute to demyelinating pathologies.Acknowledgements: Supported by Natl. MS Soc. (PEK) & NIH DA 13559 (KFH).