Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non‐histaminergic pruritus

Abstract

Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal l opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-b3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.Itching is the commonest symptom of dermatologic diseases and also a manifestation of many systemic disorders, without associated skin lesions. Itching, which provokes scratching, increases the morbidity and reduces the quality of life associated with chronic itching. 1 Itching or pruritus is an orphan symptom, without a specific efficacious treatment, such as there is for analgesics.The mechanisms and neuroscience of itch are being actively investigated, and we have studied the itching associated with antimalarial drugs, especially chloroquine (CQ). 2,3 CQ causes pruritus both in healthy volunteers, 4 as well as severe scratching in rodents, rats, 5 and mice. 6,7 The pruritus associated with CQ is greatly accentuated and generalized in patients with malaria fever, compared to the severity following CQ in people without malaria. 4,8,9 There is evidence of a genetic contribution, as the CQinduced pruritus is much more severe and generalized in blacks and people of Negroid descent, whereas pruritus is extremely rare in white patients with malaria fever receiving CQ. 2,10 Further, there is a positive correlation between the area under the intensity-time curve follow...

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

“…It can be very distressing. Antihistamine treatment is not usually very effective [97]. Hydroxychloroquine may be associated with less itching.…”

TRPA1 Channel is Involved in SLIGRL-Evoked Thermal and Mechanical Hyperalgesia in Mice

“…Recent studies have implicated TRPA1 channel as an intracellular regulator involved in itch [1,3,20,26,27,28,29,30]. The TRPA1 channel is thought to mediate chloroquine itching as the final common pathway and also to be present in sensory neurons in the skin, in mast cells, and in skin keratinocytes.…”

“…Thus, the TRPA1 is thought to mediate the transduction of itch neurotransmission in the skin to the nervous system. All these contribute to the peripheral neurotransmission of itch sensation to the DRG neurons [30].…”

“…At the basic science level, on the one hand, TRPA1 has been found to be evolutionarily conserved, with the involvement of TRPA1 orthologues in pain/itch-related behavior. On the other hand, from the point of view of the development of TRPA1 inhibitory/modulatory compounds for human clinical use, as of today, TRPA1 inhibitors have a shared feature in that they can all be improved in terms of better efficacy and fewer side effects [29,30]. Concerning the TRPA1 antagonists, there are a wide range of organic and inorganic chemicals characterized by heterogeneous chemotypes.…”

Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19

“…The major CQ/HCQ-induced adverse reactions in the gastrointestinal tract are vomiting, nausea, stomachache, diarrhea, anorexia, and weight loss, usually at the early stage of medication ( Kelley et al, 2014 ; Quach et al, 2017 ). Side effects on the skin include skin rash, pruritus, and hair loss ( Ajayi, 2019 ; Soria et al, 2015 ). Rare cases with severe side effects of renal failure and allergy reactions have been reported ( Tönnesmann, Kandolf, & Lewalter, 2013 ).…”