Abstract
Pruriceptive itch originates following activation of peripheral sensory nerve terminals when pruritogens come in contact with the skin. The ability of botulinum neurotoxins (BoNTs) to attenuate transmitter release from afferent terminals provides a rationale for studying its effect on pruritus. This study investigated the effects of BoNT/A1 and BoNT/B1 on mast cell dependent (Compound 48/80:48/80) and independent (Chloroquine:CQ) scratching. C57Bl/6 male mice received intradermal injection of 1.5 U of BoNT/A1, BoNT/B1 or saline 2, 7, 14 and 21 days prior to ipsilateral 48/80 or CQ at the nape of the neck. Ipsilateral hind paw scratching was determined using an automated recording device. The effect of BoNTs on 48/80 mediated mast cell degranulation was analyzed in human and murine mast cells and the presence of SNAREs was determined using qPCR, immunostaining and Western blot. Pre-treatment with BoNT/A1 and BoNT/B1 reduced 48/80 and CQ induced scratching behavior starting on day 2 with reversal by day 21. Both serotypes inhibited 48/80 induced mast cell degranulation. qPCR and immunostaining detected SNAP-25 mRNA and protein, respectively, in mast cells, however, Western blots did not. This study demonstrates the long-lasting anti-pruritic effects of two BoNT serotypes, in a murine pruritus model using two different mechanistically driven pruritogens. These data also indicate that BoNTs may have a direct effect upon mast cell degranulation.
Highlights
Pruritus or itch is an unpleasant sensation that promotes scratching as a primary response.Chronic itch is a debilitating and dominating symptom accompanying several disorders including skin conditions such as atopic dermatitis (AD) as well as in systemic [1,2,3]and neurological disorders [4,5]
The present study demonstrated the anti-pruritic effects of two well characterized and clinically employed botulinum neurotoxins (BoNTs) serotypes, Botulinum Toxin A1 (Botox©) and Botulinum Toxin B1 (MyoBloc©)
The present study showed that BoNTs may have a direct effect on mast cells in altering its local degranulation, and that this effect may be independent of soluble N-ethylmaleimidesensitive-factor attachment protein receptors (SNAREs) cleavage
Summary
Pruritus or itch is an unpleasant sensation that promotes scratching as a primary response.Chronic itch is a debilitating and dominating symptom accompanying several disorders including skin conditions such as atopic dermatitis (AD) as well as in systemic (renal and liver failure) [1,2,3]and neurological disorders (diabetic neuropathy and shingles) [4,5]. Many forms of itch are mediated by histamine released from mast cells that activate a subset of neurons expressing TRPV1 receptors as evidenced by the effects of TRPV1 antagonism in histamine evoked activation of dorsal root ganglion (DRG) neurons [8] and reduced histamine evoked scratching behavior [9]. Pruritogens, such as chloroquine (CQ), induce itch via mast cell-independent pathways [10]. In contrast to histamine dependent pathways, where TRPV1 functions downstream of histamine receptors to promote itch, the histamine-independent pathway utilizes TRPA1 as a key transduction channel downstream of the MrgprA3 receptor [11,12]
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