Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism

Ai, Faden

doi:10.1523/jneurosci.12-02-00425.1992

Cited by 103 publications

(51 citation statements)

References 40 publications

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“…In addition to activities at k-opioid receptors, the endogenous k-opioid receptor agonist dynorphin A-(1 ± 17) and its fragments have eects that are not associated with opioid receptors (Faden, 1992;Faden & Jacobs, 1984;Lai et al, 1998;Moises & Walker, 1985;Shukla & Lemaire, 1994 (Massardier & Hunt, 1989;Vanderah et al, 1996). We have recently shown that [des-tyrosine 1 ] dynorphin A-(2 ± 13) improved carbon monoxide (CO)-induced memory dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Microdialysis studies have demonstrated localized, dose-dependent release of glutamate and aspartate in the hippocampus not only by dynorphin A-(1 ± 17) but also by dynorphin A-(2 ± 17) (Faden, 1992). Dynorphin A-(1 ± 17) and A-(2 ± 17) are eective in potentiating NMDA currents, while the speci®c k-opioid receptor agonist U-50,488H, cannot mimic the action of dynorphin A-(1 ± 17) in periaqueductal gray cells (Caudle & Dubner, 1998;Lai et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Hiramatsu

Inoué

Ambo

et al. 2001

British J Pharmacology

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1 Tyr-D-Ala-Phe-Leu-Arg c (CH 2 NH) Arg-NH 2 (SK-9709) is a dynorphin derivative in which the peptide bond was replaced with a c (CH 2 NH) bond. In the present study, the antinociceptive eects of SK-9709 were determined in an acetic acid-induced writhing test and a hot-plate test. , s.c.). The eects of SK-9709 (s.c.) were also reversed by the selective mopioid receptor antagonist b-funaltrexamine (4.7 nmol per mouse, i.c.v.), and k-opioid receptor antagonist nor-binaltorphimine (4.9 nmol per mouse, i.t.). 4 In the hot-plate test, the antinociceptive eect of SK-9709 (s.c., i.c.v. and i.t.) was also dosedependent with the maximal peak eect at 120, 15 and 15 min similarly to the acetic acid-induced writhing test. The antinociceptive eects were dose-dependent and ED 50 values (range of 95% con®dence limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4 ± 283.0) mmol kg 71 , 6.5 (4.0 ± 10.7) and 7.4 (5.0 ± 11.0) nmol per mouse, respectively. 5 These ®ndings indicated that systemically administered SK-9709 produced long-lasting antinociceptive eects and these eects were mediated by both supra-spinal m-and spinal k-opioid receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Hiramatsu

Inoué

Ambo

et al. 2001

British J Pharmacology

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“…[19][20][21] Moreover, dynorphin administration increases extracellular levels of excitatory amino acids, including glutamate and aspartate, through a non-opioid mechanism. 22 These data suggest that whereas KOR activation may contribute to decreased locomotor function after SCI, endogenous and exogenous opioids may also engage alternative mechanisms that compromise recovery from SCI.…”

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confidence: 95%

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

Aceves

Bancroft

Aceves

2017

Journal of Neurotrauma

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Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the j-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using norBinaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 lmol) followed by morphine (0 or 0.32 lmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphineinduced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

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“…It is important to note that motor impairment potentially confounds the measurement of pain in these studies (79). Findings that dynorphin activates NMDA receptors directly, or indirectly by increasing excitatory amino acid levels (4,20,48,49,80), provide a rationale for the apparent non-opioid receptor-mediated aspects of dynorphin-induced hyperalgesia and allodynia, excitotoxicity, and exacerbated neural injury (9)(10)(11)18,20,45,49,56,79,85).…”

Section: Introductionmentioning

confidence: 99%

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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Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism

Cited by 103 publications

References 40 publications

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

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

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Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism

Cited by 103 publications

References 40 publications

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH2NH) Arg‐NH2, in mice

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH2NH) Arg‐NH2, in mice

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

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

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Product

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Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice

Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH₂NH) Arg‐NH₂, in mice