Dynorphin A decreases voltage‐dependent calcium conductance of mouse dorsal root ganglion neurones.

Macdonald, Robert L.; Werz, Mary Ann

doi:10.1113/jphysiol.1986.sp016184

Cited by 145 publications

(49 citation statements)

References 38 publications

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“…Our findings indicate that the effects of dynorphin A (1-13) at the cellular level are complex. At nanomolar concentrations, dynorphin is known to activate κ opioid receptors (51,82,92). The results of the present study additionally suggest that κ receptor activation may impart a neuroprotective effect in the presence of an excitotoxic insult-based on circumstantial evidence that κ-opioid receptor blockade intensifies dynorphin toxicity.…”

Section: Discussionsupporting

confidence: 60%

“…Although the mechanisms underlying the putative neuroprotective effects of κ receptor activation are uncertain, several possible explanations are proposed. The activation of postsynaptic κ opioid receptors typically inhibits the electrical activity of neurons by closing voltage dependent-N-type Ca 2+ channels (51,82,92). Hyperpolarizing the neuronal membrane is likely to reduce [Ca 2+ ] i and increase the excitotoxic threshold (31).…”

Section: Discussionmentioning

confidence: 99%

“…Hypothetical model for dynorphin action. At nanomolar concentrations, dynorphin A typically acts as an inhibitory opioid peptide and preferentially activates κ opioid receptors (κ) (37,51,82,92 …”

Section: Discussionmentioning

confidence: 99%

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Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Hauser

Foldes

Turbek

1999

Experimental Neurology

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Dynorphin A is an endogenous opioid peptide that preferentially activates κ opioid receptors and is antinociceptive at physiological concentrations. Levels of dynorphin A and a major metabolite, dynorphin A (1-13), increase significantly following spinal cord trauma and reportedly contribute to neurodegeneration associated with secondary injury. Interestingly, both κ opioid and N-methyl-D-aspartate (NMDA) receptor antagonists can modulate dynorphin toxicity, suggesting that dynorphin is acting (directly or indirectly) through κ opioid and/or NMDA receptor (NMDAR) types. Despite these findings, few studies have systematically explored dynorphin toxicity at the cellular level in defined populations of neurons co-expressing κ opioid and NMDA receptors. To address this question, we isolated populations of neurons enriched in both κ opioid and NMDA receptors from embryonic mouse spinal cord and examined the effects of dynorphin A (1-13) on intracellular calcium concentration ([Ca 2+ ] i ) and neuronal survival in vitro. Time-lapse photography was used to repeatedly follow the same neurons before and during experimental treatments. At micromolar concentrations, dynorphin A (1-13) elevated [Ca 2+ ] i and caused a significant loss of neurons. The excitotoxic effects were prevented by MK-801 (Dizocilpine) (10 μM), 2-amino-5-phosphopentanoic acid (AP-5) (100 μM), or 7-chlorokynurenic acid (100 μM)-suggesting that dynorphin A (1-13) was acting (directly or indirectly) through NMDA receptors. In contrast, co-treatment with (−)-naloxone (3 μM), or the more selective κ opioid receptor antagonist nor-binaltorphimine (3 μM), exacerbated dynorphin A (1-13)-induced neuronal loss; however, cell losses were not enhanced by the inactive stereoisomer (+)-naloxone (3 μM). Neuronal losses were not seen with exposure to the opioid antagonists alone (10 μM). Thus, opioid receptor blockade significantly increased toxicity, but only in the presence of excitotoxic levels of dynorphin. This provided indirect evidence that dynorphin also stimulates κ opioid receptors and suggests that κ receptor activation may be moderately neuroprotective in the presence of an excitotoxic insult. Our findings suggest that dynorphin A (1-13) can have paradoxical effects on neuronal viability through both opioid and non-opioid (glutamatergic) receptor-mediated actions. Therefore, dynorphin A potentially modulates secondary neurodegeneration in the spinal cord through complex interactions involving multiple receptors and signaling pathways.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Hauser

Foldes

Turbek

1999

Experimental Neurology

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“…153 The decrease in firing rate may be the consequence of a hyperpolarization of neurons secondary to activation of potassium conductance 154 or inhibition of voltage-dependent calcium conductance. 155,156 Selective V 2 Receptor Antagonists. Although several potent peptide VP antagonists were described in the 1980s, [120][121][122] none has emerged as a clinically useful aquaretic agent because of their low oral bioavailability and partial agonist activity.…”

Section: Aquaretic Drugsmentioning

confidence: 99%

Hyponatremia in cirrhosis: From pathogenesis to treatment

et al. 1998

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“…Fast synaptic transmission at mossy fiber synapses has been shown to depend on both N-and P-type Ca 2ϩ channels (Castillo et al, 1994b), and under normal conditions mossy fiber responses are maximally inhibited by dynorphin by 40%. Because it is well established that dynorphin can inhibit Ca 2ϩ channels (Macdonald and Werz, 1986;Gross and Macdonald, 1987;Attali et al, 1989), one possible explanation for this ceiling effect is that dynorphin eliminates a particular type of Ca 2ϩ channel. We were unable, however, to alter the magnitude of this inhibition by selectively blocking N-or P-type Ca 2ϩ channels with either -CgTx or -Aga IVA (see also Simmons et al, 1995).…”

Section: The Role Of Camentioning

confidence: 99%

Characterizing the Site and Mode of Action of Dynorphin at Hippocampal Mossy Fiber Synapses in the Guinea Pig

et al. 1996

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Extracellular field potential recordings from the CA3 region in guinea pig hippocampal slices were used to study the release and action of dynorphin at the mossy fiber synapse. Dynorphin A(1-17) or U69593 inhibited mossy fiber synaptic responses in preparations in which the CA3 region was surgically isolated from the rest of the hippocampus. This inhibition was completely reversed by the 1 selective antagonist nor-BNI, thus establishing the presence of functional 1 receptors in CA3. Inhibitory effects of dynorphin on mossy fiber responses were unaltered in the presence of the N-or P-type Ca 2ϩ channel blockers, -CgTx or -Aga IVA, respectively. This indicates that the action of dynorphin is independent of the particular type of Ca 2ϩ channel that mediates transmitter release at the mossy fiber terminal. Heterosynaptic inhibition of mossy fiber responses was observed in the presence of nifedipine, -CgTx, or -Aga IVA, indicating that dynorphin release does not depend specifically on L-, N-, or P-type Ca 2ϩ channels. The blockade of heterosynaptic inhibition by the membranepermeant Ca 2ϩ chelator EGTA-AM suggests the involvement of a slow Ca 2ϩ -dependent process in dynorphin release. On the basis of a variety of experimental evidence, we propose that the time course of heterosynaptic inhibition is determined primarily by the time course of clearance of dynorphin in the extracellular space.

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Dynorphin A decreases voltage‐dependent calcium conductance of mouse dorsal root ganglion neurones.

Cited by 145 publications

References 38 publications

Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Hyponatremia in cirrhosis: From pathogenesis to treatment

Characterizing the Site and Mode of Action of Dynorphin at Hippocampal Mossy Fiber Synapses in the Guinea Pig

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