Peptidase inhibitors improve recovery of substance P and calcitonin gene-related peptide release from rat spinal cord slices

Chen, Joanne J.; Barber, Lisa A.; Dymshitz, Julia; Vasko, Michael R.

doi:10.1016/0196-9781(95)02091-8

Cited by 36 publications

(31 citation statements)

References 29 publications

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“…Aminopeptidases are also thought to contribute to the degradation of neurokinins. In particular, the aminopeptidase inhibitor bacitracin was reported in one study (Mauborgne et al, 1991) as the most potent agent protecting SP from degradation, and has been used together with inhibitors of NEN and DCP to improve the recovery of released SP (Malcangio & Bowery, 1993;Chen et al, 1996;Malcangio et al, 1997;Lever & Malcangio, 2002). However, none of the aminopeptidase inhibitors that we tested, including bacitracin, increased NK1R internalization produced by a low concentration of SP.…”

Section: Jcg Marvizón Et Almentioning

confidence: 95%

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

Marvizón¹,

Wang

Lao³

et al. 2003

British J Pharmacology

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1 The ability of peptidases to restrict neurokinin 1 receptor (NK1R) activation by exogenously applied or endogenously released neurokinins was investigated by measuring NK1R internalization in rat spinal cord slices. 2 Concentration -response curves for substance P and neurokinin A were obtained in the presence and absence of 10 mM thiorphan, an inhibitor of neutral endopeptidase (EC 3.4.24.11), plus 10 mM captopril, an inhibitor of dipeptidyl carboxypeptidase (EC 3.4.15.1). These inhibitors significantly decreased the EC 50 of substance P to produce NK1R internalization from 32 to 9 nM, and the EC 50 of neurokinin A from 170 to 60 nM. 3 Substance P was significantly more potent than neurokinin A, both with and without these peptidase inhibitors. 4 In the presence of peptidase inhibitors, neurokinin B was 10 times less potent than neurokinin A and 64 times less potent than substance P (EC 50 ¼ 573 nM). 5 Several aminopeptidase inhibitors (actinonin, amastatin, bacitracin, bestatin and puromycin) failed to further increase the effect of thiorphan plus captopril on the NK1R internalization produced by 10 nM substance P. 6 Electrical stimulation of the dorsal root produced NK1R internalization by releasing endogenous neurokinins. Thiorphan plus captopril increased NK1R internalization produced by 1 Hz stimulation, but not by 30 Hz stimulation. 7 Therefore, NEN and DCP restrict NK1R activation by endogenous neurokinins when they are gradually released by low-frequency firing of primary afferents, but become saturated or inhibited when primary afferents fire at a high frequency.

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Section: Jcg Marvizón Et Almentioning

confidence: 95%

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

Marvizón¹,

Wang

Lao³

et al. 2003

British J Pharmacology

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“…The amount of iCGRP released in each incubation was measured by a radioimmunoassay. The minimum amount of iCGRP detected by the radioimmunoassay is 5 fmol with a 95% confidence interval (29). After the release protocol, the remaining peptide content in each well was determined by exposing the cells to 2 N acetic acid for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

Wilson

Schmutzler

Brittain

et al. 2012

Journal of Biological Chemistry

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Background: N-type Ca 2ϩ channels (CaV2.2) are clinically validated targets for chronic pain. Results: Two peptides from CaV2.2 and CaV1.2 perturb binding to a regulatory protein, CRMP2, inhibit calcium influx, and attenuate mechanical hyperalgesia in a rodent model of drug-induced chronic pain. Conclusion: Ca 2ϩ channel peptides block drug-and nerve injury-induced chronic pain. Significance: Ca 2ϩ channel peptide therapeutics can be useful in mitigating chronic pain.

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“…The evoked release of CGRP was done according to Chen et al (1996) and as described previously (Gardell et al, , 2003b. The rats were killed by anesthetic overdose 18 h after the last injection of vehicle or epoxomicin.…”

Section: Methodsmentioning

confidence: 99%

Control of Chronic Pain by the Ubiquitin–Proteasome System in the Spinal Cord

et al. 2007

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Chronic pain is maintained in part by long-lasting neuroplastic changes in synapses and several proteins critical for synaptic plasticity are degraded by the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors administered intrathecally or subcutaneously prevented the development and reversed nerve injury-induced pain behavior. They also blocked pathological pain induced by sustained administration of morphine or spinal injection of dynorphin A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked mechanical allodynia and thermal hyperalgesia in all three pain models although they did not modify responses to mechanical stimuli, but partially inhibited responses to thermal stimuli in control rats. In the spinal cord, these compounds abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP) release and dynorphin A upregulation, both elicited by nerve injury. Model experiments demonstrated that the inhibitors may act directly on dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of proteasome inhibitors on chronic pain were apparently mediated through several cellular mechanisms indispensable for chronic pain, including those of dynorphin A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS proteins were reduced in animals with neuropathic pain, suggesting that UPS downregulation, like effects of proteasome inhibitors, counteracts the development of chronic pain. The inhibitors did not produce marked or disabling motor disturbances at doses that were used to modify chronic pain. These results suggest that the UPS is a critical intracellular regulator of pathological pain, and that UPS-mediated protein degradation is required for maintenance of chronic pain and nociceptive, but not non-nociceptive responses in normal animals.

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Peptidase inhibitors improve recovery of substance P and calcitonin gene-related peptide release from rat spinal cord slices

Cited by 36 publications

References 29 publications

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

Control of Chronic Pain by the Ubiquitin–Proteasome System in the Spinal Cord

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