Involvement of nitric oxide in serotonin-induced scratching in mice

Ostadhadi, Sattar; Haj-Mirzaian, Arvin; Azimi, Ehsan; Mansouri, Parvin; Dehpour, Ahmad Reza

doi:10.1111/ced.12605

Cited by 19 publications

(17 citation statements)

References 23 publications

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“…Our studies in BMDMs and BMMCs confirm that overexpression of GCH1 enhances BH4, NO and H 2 O 2 release and mast cell degranulation, but the downstream path from BH4 to degranulation is still unknown. It has been shown that balances of NO/H 2 O 2 impact on the release of biogenic amines from mast cells in itching models suggesting a redox dependent mechanism. It is noteworthy that protein kinase C dependent degranulation involves phosphorylation, hence activation of GCH1 suggesting that BH4 is produced on PKC activation to replenish the mediator content of secretory vesicles.…”

Section: Discussionmentioning

confidence: 99%

Mast cell tetrahydrobiopterin contributes to itch in mice

Zschiebsch

Fischer

Wilken-Schmitz

et al. 2018

J Cellular Molecular Medi

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GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron‐specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non‐neuronal source of BH4 that may contribute to BH4‐dependent phenotypes, we studied here the contribution of myeloid‐derived BH4 to pain and itch in lysozyme M Cre‐mediated GCH1 knockout (LysM‐GCH1−/−) and overexpressing mice (LysM‐GCH1‐HA). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM‐driven GCH1 knockout reduced, and its overexpression increased the scratching response in Compound 48/80 and hydroxychloroquine‐evoked itch models, which involve histamine and non‐histamine dependent signalling pathways. Mechanistically, GCH1 overexpression increased BH4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM‐driven GCH1 knockout had opposite effects, and pharmacologic inhibition of GCH1 provided even stronger itch suppression. Inversely, intradermal BH4 provoked scratching behaviour in vivo and BH4 evoked an influx of calcium in sensory neurons. Together, these loss‐ and gain‐of‐function experiments suggest that itch in mice is contributed by BH4 release plus BH4‐driven mediator release from myeloid immune cells, which leads to activation of itch‐responsive sensory neurons.

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Section: Discussionmentioning

confidence: 99%

Mast cell tetrahydrobiopterin contributes to itch in mice

Zschiebsch

Fischer

Wilken-Schmitz

et al. 2018

J Cellular Molecular Medi

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“…Activation of this pathway is also associated with increased production of NO (28). NO is associated with itch while inhibition of NOS suppresses itch (25, 26, 30). We reported recently that the NO/cGMP pathway participates in CQ-induced itch (30).…”

Section: Discussionmentioning

confidence: 99%

“…NO functions as a neurotransmitter in itch (25, 26, 38, 51). Similar to our findings with CQ, previous studies have shown that NO enhances substance P-induced itch in mice (25).…”

Section: Discussionmentioning

confidence: 99%

“…Intrathecal application of the NMDAR antagonists dizocilpine (MK-801) or D (−) -2-amino- 5-phosphonovalerate (APV) prevented intracutaneous histamine-induced expansion of mechanical receptive fields in rats (24). Separately, it has been shown that administration of a nitric oxide (NO) donor to skin enhances substance P-induced itch in mice (25), while serotonin-induced itch was inhibited by systemic nitric oxide synthase (NOS) inhibitors (26). …”

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confidence: 99%

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Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice

Haddadi

Foroutan²,

Ostadhadi³

et al. 2017

Acta Derm Venerol

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Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scratching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior.

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“…The advantageous property of PPAR-γ agonists on itching in various dermatological disorders has been reported by many clinical studies (Ellis et al, 2000;Pershadsingh et al, 1998;Sepmeyer et al, 2007). Our previous experimental study demonstrated that chliorquine (Foroutan et al,6 2015) serotonin can induce scratching in mice (Ostadhadi et al, 2015a;Ostadhadi et al, 2015b;Rajaba et al, 2014) and the protective anti-scratching effect of pioglitazone in serotonin-induced scratching is mediated through PPAR-γ receptor and is possibly nitric oxide dependent (Rajaba et al, 2014). However future studies are required in order to elaborate the possible peripheral and/or central anti-pruritic mechanisms of PPAR-γ (Fig.…”

Section: Ppar-γ and Pruritusmentioning

confidence: 87%