A zinc deficiency leads to non-inflammatory pruritus by modifying opioid receptor signaling.

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.