title: Hesperidin induces antinociceptive effect in mice and its aglycone, hesperetin, binds to μ-opioid receptor and inhibits GIRK1/2 currents.
abstract: This paper extended the evaluation of the depressant and antinociceptive activities of hesperidin in order to determine its effectiveness by the intraperitoneal and oral routes, its pharmacological interaction with diverse pathways of neurotransmission and the role of its aglycone, hesperetin. The capacity of hesperidin and hesperetin to bind to μ-opioid receptor and their actions on μ-opioid receptor co-expressed with GIRK1/GIRK2 channels (G protein-activated inwardly rectifying K+ channels) in Xenopus laevis oocytes were also determined. Hesperidin exhibited a depressant activity in the hole board and locomotor activity tests, antinociceptive activities in the abdominal writhing and hot plate tests and no motor incoordination in the inverted screen and rotarod assays, only by the intraperitoneal route. Hesperetin did not show any effects in vivo in mice in these models, but in vitro it displaced the [³H]DAMGO binding with low-affinity and inhibited inward currents through the expressed GIRK1/2 channels. Although hesperidin actions in vivo demonstrated to be mediated by an opioid mechanism of action, it failed to directly bind to and activate the μ-opioid receptor or produce any change on inward GIRK1/2 currents in vitro. However, it should be considered that hesperidin may be metabolized, possibly resulting in crucial changes in its biological activity.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Loscalzo
authors.forename: Tin T
authors.initials: TT
authors.lastname: Yow
authors.forename: Cristina
authors.initials: C
authors.lastname: Wasowski
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Mariel
authors.initials: M
authors.lastname: Marder
mesh_terms: D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D006569:Hesperidin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; D026902:Potassium Channel Blockers; D017450:Receptors, Opioid, mu; D006569:Hesperidin; C013015:hesperetin