Elsevier

Neuropeptides

Volume 32, Issue 1, February 1998, Pages 87-95
Neuropeptides

Ifenprodil blocks the excitatory effects of the opioid peptide dynorphin 1–17 on NMDA receptor-mediated currents in the CA3 region of the guinea pig hippocampus

https://doi.org/10.1016/S0143-4179(98)90022-1Get rights and content

Abstract

This study found that dynorphin had a biphasic concentration response relationship on N-methyl-Daspartate (NMDA) receptor-mediated currents in the CA3 region of the guinea pig hippocampal slice. A previous study demonstrated that the inhibitory effect was mediated by a kappa2 opioid receptor. In the present study, the polyamine site antagonist ifenprodil converted dynorphin's biphasic concentration response relationship to a monophasic inhibitory curve. The polyamine diethylenetriamine also blocked dynorphin's excitatory actions. The combination of dynorphin 1–17 and naloxone produced neurotoxicity, presumably as a result of dynorphin's excitatory actions on NMDA receptors. In addition, the release of endogenous dynorphin from mossy fibers in the presence of naloxone injured the cells. Ifenprodil prevented the neurotoxicity of both applied and released dynorphin. These findings suggest that dynorphin acts at a polyamine site to produce its excitatory effects and, further, suggest that dynorphin may mediate some neuropathologies through its interaction at this site.

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      Therefore, the NMDA receptor appears to be a likely mediator of many of the antinociceptive actions of opioids in general and a likely mediator of many non-analgesic actions of dynorphins in particular (Lai et al., 2001; Laughlin et al., 1997; Vanderah et al., 1996), as indicated in the sections that follow. Considerable evidence indicates that κ-opioid ligands interact directly with the NMDA receptor (Hauser et al., 1999; Schwarzer, 2009; Shukla and Lemaire, 1994; Tang et al., 1999) either at a glycine site (Voorne et al., 2007) or quite possibly at multiple binding sites (Caudle and Dubner, 1998; Chen et al., 1995; Laughlin et al., 2001; Tan-No et al., 2002; Woods et al., 2006; Zhang et al., 1997). A distinct high affinity dynorphin binding site has also been detected on the NMDA receptor in rat cortex (Tang et al., 1999).

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