The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 9 • October 2013

Surprise! Kappa Opioid Receptors Mediate the
Antidepressant-Like Activity of Hesperidin in Mice

Who would have thought it? That hesperidin could exhibit anti-depressant effects in mice subjected to the forced swim test and do so by interacting with the kappa opioid receptor. But that’s one thing about biomedical science—there are always lots of surprises.

The kappa opioid receptor is one of the three currently known opioid receptors, that also include mu and delta opioid receptors. Hesperidin, a naturally occurring flavonone glycoside, is found in rich quantities in citrus fruits and has been reported to have antioxidant, neuroprotective, and anticancer effects. An earlier paper2 reported that in traditional Mexican medicine, infusion of flowers of the Citrus genera are used as a sedative to treat insomnia. This paper2 explored the sedative effects of Citrus; the authors reported that, in an earlier study, hesperidin in the methanol extract of Citrus sinensis was identified as the sedative active principle of the plant. Others had described the involvement of opioid receptors to the behavioral and antinociceptive (anti-pain) effects of hesperidin.

The immobility period of the mice subjected to the forced swim test (freezing as a result of fear) was significantly reduced by treatment with hesperidin at doses of 0.1, 0.3, and 1 mg/kg.1 Pretreatment with naloxone (a nonselective opioid receptor antagonist) reversed the antidepressant-like effect of hesperidin in that study.


  1. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol. 698:286-91 (2013).
  2. Guzman-Gutierrez and Navarrete. Pharmacological exploration of the sedative mechanism of hesperidin identified as the active principle of Citrus sinensis flowers. Planta Med. 75:295-301 (2009).

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