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Updated: Jun 19, 2026

Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors
Published on: September 27, 2019
A zinc deficiency leads to non-inflammatory pruritus by modifying opioid receptor signaling
Hozumi Sano1, Reiko Kamijima2, Mikiro Takaishi2
1Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan; Sano Dermatology Office, Nishinomiya, Japan.
Background:
Pruritus is a major unpleasant sensation due to skin inflammation (inflammatory pruritus, IP), or due to a neurological disturbance despite the absence of objective symptoms of inflammation (non-inflammatory pruritus, NIP). It remains unknown whether a zinc deficiency (ZD) is related to pruritus.
Objective:
To explore whether patients with IP or NIP showed alterations of serum zinc levels and evaluate the role of zinc in pruritus using an animal model.
Methods:
Serum levels of zinc were compared between IP, NIP and non-pruritic controls. Patients with ZD were supplemented with oral zinc. Pruritus was evaluated using a numerical rating scale. Mice were treated with the mu opioid agonist morphine to induce NIP. Nalfurafine, a kappa opioid receptor agonist, was administrated prior to morphine treatment.
Results:
Serum zinc levels were decreased in pruritic patients compared to non-pruritic controls and were significantly lower in NIP than IP patients. All NIP patients showed a ZD, and their itch symptoms were drastically resolved by zinc supplementation, along with normalization of zinc levels. ZD mice had a significantly higher sensitivity to morphine, compared to control mice. Treatment with nalfurafine ameliorated the morphine-induced pruritus in ZD mice.
Conclusion:
Our data strongly suggest that a ZD is an independent cause of NIP, which could be resolved by zinc supplementation. In addition, mouse model revealed that zinc plays a critical role in modification of opioid receptor-mediated signaling. This study reveals for the first time that zinc is crucially related to pruritus via opioid receptors.
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