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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

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

Alrashdi, Ibrahim, Alsubaiyel, Amal, Chan, Michelle, Battell, Emma E., Ennaceur, Abdelkader, Nunn, Miles A., Weston-Davies, Wayne, Chazot, Paul and Obara, Ilona (2022) Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice. Frontiers in Pharmacology, 13.

Item Type: Article


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.

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More Information

Depositing User: Abdelkader Ennaceur


Item ID: 14672
Identification Number:
Official URL:

Users with ORCIDS

ORCID for Abdelkader Ennaceur: ORCID iD
ORCID for Paul Chazot: ORCID iD
ORCID for Ilona Obara: ORCID iD

Catalogue record

Date Deposited: 17 Mar 2022 14:13
Last Modified: 17 Mar 2022 14:15


Author: Abdelkader Ennaceur ORCID iD
Author: Paul Chazot ORCID iD
Author: Ilona Obara ORCID iD
Author: Ibrahim Alrashdi
Author: Amal Alsubaiyel
Author: Michelle Chan
Author: Emma E. Battell
Author: Miles A. Nunn
Author: Wayne Weston-Davies

University Divisions

Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Biomedical Sciences
Psychology > Neuropsychology
Sciences > Pharmacy and Pharmacology

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