Structure–Activity Analysis of Dynorphin A Toxicity in Spinal Cord Neurons: Intrinsic Neurotoxicity of Dynorphin A and Its Carboxyl-Terminal, Nonopioid Metabolites

Hauser, Kurt F.; Knapp, Pamela E.; Turbek, Carol S.

doi:10.1006/exnr.2000.7580

Cited by 39 publications

(45 citation statements)

References 58 publications

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“…This effect was significantly stronger with ACP than with AC or CP; it was also stronger than with administration of AP, but not significantly so. These results demonstrate that ACP is required to inhibit degradation of intact Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and that any residual pair of peptidases inactivates substantial amounts of Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This is in good agreement with the results of an earlier study by this group demonstrating that the antinociceptive potency of Dyn A (1-17) was Both the present and earlier studies demonstrated that LE (IC 50 : 1.74 nM) [36] showed greater potency than Dyn A (1-17) (IC 50 : 4.53 nM) under pretreatment with ACP in isolated MVD preparation.…”

Section: Discussionmentioning

confidence: 70%

“…[21], and nor-BNI (20 mg/kg, subcutaneously) [23] were injected at 20 min, 15 min, 30 min, and 24 hr, respectively, before i.t. administration of Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) or Dyn A (1-13).…”

Section: Selective or Non-selective Opioid Receptor Antagonistsmentioning

confidence: 99%

“…Earlier research on the inhibitory potency of LE or Dyn A (1)(2)(3)(4)(5)(6)(7)(8) against electrically-evoked contractions in mouse vas deferens (MVD) demonstrated that it was enhanced by exposure to various combinations of amastatin (A), captopril (C), and phosphoramidon (P) [14] [15]. These results correspond (1-17)-induced antinociception by more than 500- [14], 100- [16], and 30-fold [17], respectively.…”

Section: Introductionmentioning

confidence: 96%

“…Dynorphin (Dyn) A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) and (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) interacts with both opioid and N-methyl-D-aspartate (NMDA) receptors: their N-terminals activate the former with high affinity, while its C-terminals activate the latter with low affinity [1] [2] [3] [4].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level

Matsuda¹,

Yoshikawa²,

Kan³

et al. 2017

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Our group has earlier demonstrated that three enzymes sensitive to peptidase inhibitors (PIs), amastatin (A)-, captopril (C)-, and phosphoramidon (P), played an important role in inactivation of enkephalins at the spinal level. Dynorphin-converting enzyme (DCE) hydrolyzes dynorphin (Dyn) A (1-17) or Dyn A (1-13) mainly at the Arg 6 -Arg 7 bond. Dynorphin A and its derived peptides interact with opioid and glutamate receptors at their N-and C-terminals, respectively. The purpose of the present study was to evaluate the antinociceptive potency and toxicity of intrathecal administered Dyn A (1-17), Dyn A (1-13), or Dyn A (1-6) under pretreatment with ACP and/or the DCE inhibitor p-hydroxymercuribenzoate (PHMB). The effect of these PIs on Dyn A (1-17)-induced inhibition of electrically-evoked contractions in mouse vas deferens was also investigated. The inhibitory potency of Dyn A (1-17) on electrically-evoked contractions in mouse vas deferens under pretreatment with ACP was higher than that with AC, AP, or CP. Pretreatment with ACP augmented Dyn A (1-17) or (1-13)-induced antinociception by approximately 50-or 30-fold with no sign of allodynia when administered intrathecally at low doses. Pretreatment with ACP and PHMB induced neuropathy. These findings showed that intrathecal administration of low-dose Dyn A (1-17) or DynA (1-13) increased antinociception under pretreatment with ACP, but without signs of allodynia in rat.

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Section: Discussionmentioning

confidence: 70%

Section: Selective or Non-selective Opioid Receptor Antagonistsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level

Matsuda¹,

Yoshikawa²,

Kan³

et al. 2017

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“…While many, but certainly not all of the reported properties of dynorphins at the NMDA receptor are excitatory, a distinct, high affinity dynorphin binding site has been detected on the NMDA receptor in rat cortex (Tang et al, 1999). The excitatory and often neurotoxic actions of dynorphins at NMDA receptors is well documented in dorsal horn neurons of the spinal cord (Hauser et al, 2001;Lai et al, 2001;Laughlin et al, 1997;2001;Shukla and Lemaire, 1994). Dynorphins also produce antianalgesic effects by way of interactions at the NMDA receptor (Arcaya et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Bi-phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: Partial blockade by an N-Methyl-d-Aspartate (NMDA)-receptor antagonist

Sahley

Anderson

Chernicky

2008

European Journal of Pharmacology

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Dynorphins, glutamate, and glutamate-sensitive N-Methyl-D-Aspartate (NMDA) receptors exist in the mammalian cochlea. Dynorphins produce neural excitation and excitotoxic effects in the spinal cord through a κ-opioid facilitation of NMDA receptor sensitivity to glutamate. The κ-opioid receptor drug agonists N-dimethylallyl-normetazocine [(-)-pentazocine (50 mmol)] and trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide [U-50488H (100 mmol)] were administered across the cochlear round window membrane in the chinchilla. Each drug produced significant post-baseline amplitude changes in the click-evoked auditory nerve compound action potential. Amplitude changes at threshold amounted to increases in sensitivity that ranged from 4-8 decibels, measured in sound pressure level (dB SPL). The large neural amplitude increases at threshold were accompanied by progressively smaller amplitude changes at 5 and 10 dB above threshold (dB SL). However, at stimulus intensities ≥ 20dB SL, post-baseline neural amplitudes were suppressed to levels below baseline and control values. These bi-phasic intensity-dependent neural amplitude changes have never before been observed following i.v. administered (-)-pentazocine in this species. Finally, the bi-phasic neural amplitude changes in U-50488H-treated (100 mmol) animals were partially blocked (except at 20dB SL), following a round window pretreatment with the NMDA receptor drug antagonist, dizocilpine hydrogen maleate [(+)-MK-801 (8 mmol)]. Our data suggests that endogenous dynorphins within lateral efferent olivocochlear neurons differentially modulate auditory neural excitation, possibly through cochlear NMDA receptors and glutamate. The role played by lateral efferent opioid neuromodulation at cochlear NMDA receptors, is discussed.

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Pharmacotherapy for Spinal Cord Injury

Casha¹,

Silvaggio²,

Hurlbert³

2007

Surgical Management of Spinal Cord Injury

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Structure–Activity Analysis of Dynorphin A Toxicity in Spinal Cord Neurons: Intrinsic Neurotoxicity of Dynorphin A and Its Carboxyl-Terminal, Nonopioid Metabolites

Cited by 39 publications

References 58 publications

Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level

Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level

Bi-phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: Partial blockade by an N-Methyl-d-Aspartate (NMDA)-receptor antagonist

Pharmacotherapy for Spinal Cord Injury

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