Effects of Chloroquine on Release of Mediators from Mast Cells

Green, Karen B.; Lim, Henry W.

doi:10.1159/000210804

Cited by 15 publications

(9 citation statements)

References 14 publications

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“…The residual CQ-induced scratching behavior seen in mutant animals is likely due to an indirect effect on skin sensory nerves. Both our behavioral data from SASH mice and complete elimination of CQ-sensitive neurons in Mrgpr-clusterΔ −/− DRG support this notion and suggest that the residual CQ-induced response in Mrgpr-clusterΔ −/− mice results from degranulation of skin mast cells caused by the drug, a phenomenon observed in previous studies (Green and Lim, 1989; Nosal et al, 1991). …”

Section: Discussionsupporting

confidence: 87%

“…Previous studies have indicated that CQ can cause mast cell degranulation (Green and Lim, 1989; Nosal et al, 1991). To determine if this effect on mast cells contributes to CQ-evoked scratching behavior, we repeated the experiment on SASH mice, which lack mast cells due to a chromosomal inversion in the regulatory element of the Kit gene (Yamazaki et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

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Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Liu

Tang

Surdenikova

et al. 2009

Cell

689

936

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SUMMARY The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side-effect of this widely used anti-malarial drug. Here we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and co-express Gastrin-Releasing Peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Liu

Tang

Surdenikova

et al. 2009

Cell

689

936

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“…The latter are highly sensitive to oxidative modifications and therefore potential targets of BH4‐mediated strengthening of HCQ‐evoked pruriceptive effects. In addition, HCQ is known to cause mast cell degranulation of classical mediators and of phospholipid mediators . Hence, in addition to GCH1 dependent degranulation of typical prurigenic mediators, release of BH4/NO per se appears to promote pruriceptor stimulation as a kind of co‐stimulant, which enhances effects of HCQ and other mediators on sensory nerve terminals.…”

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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“…Sensory neurons may thus not be the only source of NO following intradermal CQ injection. CQ also induces mast cell degranulation, (64, 65) releasing mediators that interact with afferent nerve fibers in the skin.…”

Section: Discussionmentioning

confidence: 99%

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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Effects of Chloroquine on Release of Mediators from Mast Cells

Cited by 15 publications

References 14 publications

Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Mast cell tetrahydrobiopterin contributes to itch in mice

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

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