Characterization of a chloroquine‐induced canine model of pruritus and skin inflammation

Abstract

Background Chloroquine (CQ) is a prototypical systemic and intradermal pruritogen for histamine‐independent (nonhistaminergic) itch in mice and humans. The predictive validity of this model is poorly documented in dogs. Hypothesis/Objective To determine pruritogenic and inflammatory effects of systemic and i.d. CQ injections in healthy dogs. Animals Ten healthy purpose‐bred laboratory beagles. Methods and materials All dogs were randomized to receive i.d. (200 and 400 µg/site), intravenous (2 mg/kg) and subcutaneous (3 mg/kg) CQ injections. Dogs were video‐recorded for 30 min after i.d. injections and for 300 min after i.v. and s.c. injections. Buffered saline injections served as controls for each route. Global wheal scores were evaluated at 30 min post‐i.d. injection by a blinded investigator. Results All dogs showed wheal and erythema at the CQ i.d. injection sites; global wheal scores of each CQ concentration were significantly increased compared to placebo (P ≤ 0.05). Blinded evaluation revealed no significant increase in generalized pruritic behaviour (pruritic seconds) after i.v. or s.c. administration of CQ. Intradermal injections induced mild localized acute pruritic behaviours at the site of injections at 200 µg (P = 0.06) and 400 µg (P = 0.27) CQ in dogs. Conclusion and clinical significance To the best of the authors’ knowledge, this is the first report which shows that i.d. CQ injections may induce acute inflammation in healthy dogs. By contrast to the systemic CQ‐induced pruritus reported previously in healthy mice and dogs, no significant pruritic behaviours were observed after CQ injection, regardless of the route of administration.

Cytokine transcriptome profiling in acute experimental canine atopic dermatitis skin lesions after IL‐31 inhibition with lokivetmab

“…Based on their active gene expression levels and significant upregulation compared to their expression at baseline, we identified IL‐33, IL‐13, CCL17, and IL‐9, and potentially IL‐6 and CCL22, as possible targets for inhibition which might complement the action of LKV. To support this, the upregulation of mRNA or protein expression of IL‐33, IL‐13, and CCL17 has been reported in the skin or sera of client‐owned dogs with AD compared to healthy dogs in multiple studies 27–31 . Some of these cytokines and chemokines (e.g., IL‐33, CCL17, IL‐6, CCL22) are produced at a very early stage of AD acute flare induction, which is likely to be even before Th2 cells produce IL‐31 32 .…”

“…To support this, the upregulation of mRNA or protein expression of IL-33, IL-13, and CCL17 has been reported in the skin or sera of client-owned dogs with AD compared to healthy dogs in multiple studies. [27][28][29][30][31] Some of these cytokines and chemokines (e.g., IL-33, CCL17, IL-6, CCL22) are produced at a very early stage of AD acute flare induction, which is likely to be even before Th2 cells produce IL-31. 32 Therefore, the expression of mRNA was not likely to have been affected by IL-31 inhibition.…”

Update on the role of cytokines and chemokines in canine atopic dermatitis

“…Interestingly, the results of these studies revealed multipolar immunological axis upregulation (Th1, Th2, Th17 and Th22) in cAD as is found in humans with AD. [10][11][12][13][14] This indicates that cytokine network activation in AD is, in fact, no longer considered to simply involve a specific group of cytokines (i.e. upregulation of only Th2 cytokines) and is instead the interplay between a large number of cytokines.…”

Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities

“…Concerning pruritus, CQ can bind to and activate the masrelated G protein-coupled receptors MrgprA3/MrgprX, which can be coupled to PLC-b3 or TRPA1 and so initiate pruritus [117]. The activation of this receptor is the main known mechanism of CQ-induced pruritus and even constitutes an animal model of itch [118]. More, opiate receptor, serotonin receptor, N-methyl-D-aspartate receptors, and gastrin-releasing peptide receptor are probably involved in this iatrogen itch, but exact mechanisms are unknown [119].…”