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Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice

Alrashdi, Ibrahim; Alsubaiyel, Amal; Chan, Michele; Battell, Emma E.; Ennaceur, Abdel; Nunn, Miles A.; Weston-Davies, Wayne; Chazot, Paul L.; Obara, Ilona

Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice Thumbnail


Ibrahim Alrashdi

Amal Alsubaiyel

Michele Chan

Emma E. Battell

Abdel Ennaceur

Miles A. Nunn

Wayne Weston-Davies

Ilona Obara


Votucalis is a biologically active protein in tick (R. appendiculatus) saliva, which specifically binds histamine with high affinity and, therefore, has the potential to inhibit the host’s immunological responses at the feeding site. We hypothesized that scavenging of peripherally released endogenous histamine by Votucalis results in both anti-itch and anti-nociceptive effects. To test this hypothesis, adult male mice were subjected to histaminergic itch, as well as peripheral nerve injury that resulted in neuropathic pain. Thus, we selected models where peripherally released histamine was shown to be a key regulator. In these models, the animals received systemic (intraperitoneal, i.p.) or peripheral transdermal (subcutaneous, s.c. or intraplantar, administrations of Votucalis and itch behavior, as well as mechanical and thermal hypersensitivity, were evaluated. Selective histamine receptor antagonists were used to determine the involvement of histamine receptors in the effects produced by Votucalis. We also used the spontaneous object recognition test to confirm the centrally sparing properties of Votucalis. Our main finding shows that in histamine-dependent itch and neuropathic pain models peripheral (s.c. or administration of Votucalis displayed a longer duration of action for a lower dose range, when compared with Votucalis systemic (i.p.) effects. Stronger anti-itch effect was observed after co-administration of Votucalis (s.c.) and antagonists that inhibited peripheral histamine H1 and H2 receptors as well as central histamine H4 receptors indicating the importance of these histamine receptors in itch. In neuropathic mice, Votucalis produced a potent and complete anti-nociceptive effect on mechanical hypersensitivity, while thermal (heat) hypersensitivity was largely unaffected. Overall, our findings further emphasize the key role for histamine in the regulation of histaminergic itch and chronic neuropathic pain. Given the effectiveness of Votucalis after peripheral transdermal administration, with a lack of central effects, we provide here the first evidence that scavenging of peripherally released histamine by Votucalis may represent a novel therapeutically effective and safe long-term strategy for the management of these refractory health conditions.


Alrashdi, I., Alsubaiyel, A., Chan, M., Battell, E. E., Ennaceur, A., Nunn, M. A., …Obara, I. (2022). Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice. Frontiers in Pharmacology, 13, Article 846683.

Journal Article Type Article
Acceptance Date Feb 15, 2022
Online Publication Date Mar 8, 2022
Publication Date 2022
Deposit Date Mar 31, 2022
Publicly Available Date Mar 31, 2022
Journal Frontiers in Pharmacology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 13
Article Number 846683


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Copyright Statement
© 2022 Alrashdi, Alsubaiyel, Chan, Battell, Ennaceur, Nunn, Weston-Davies, Chazot and Obara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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