title: Antinociceptive effect of hydroalcoholic extract and isoflavone isolated from Polygala molluginifolia in mice: evidence for the involvement of opioid receptors and TRPV1 and TRPA1 channels.
abstract: OBJECTIVE
  The plants of the genus Polygala (Polygalaceae) have been used for a long time in folk medicine to treat pain and inflammation. The species Polygala molluginifolia is native to southern Brazil and is popularly known as "cânfora". The presented study analyzes the antinociceptive effect of hydroalcoholic extract from Polygala molluginifolia (HEPm) and an isoflavone (ISO) isolated from the extract, in behavioral models of pain in mice, as well as the mechanism underlying this effect.
  
  
  METHODS
  The phytochemical analysis of HEPm was performed through a capillary electrophoresis analysis and colorimetric test. The antinociceptive effects of HEPm and ISO (10-1000 mg/kg, i.g.) were evaluated by applying the formalin test; mechanical and thermal hyperalgesia to postoperative pain in mice. The possible involvement of opioid receptors, TRPV1 and TRPA1 channels in the antinociceptive effect of HEPm and ISO were also evaluated. Finally, the nonspecific effects of HEPm and ISO were evaluated by measuring locomotor activity (Open-field Test) and corporal temperature.
  
  
  RESULTS
  The 5,3',4'-trihydroxy-6″,6″-dimethylpyrano[2″,3″:7,6] isoflavone (ISO) was identified in HEPm by capillary electrophoresis analysis and selected for the experimental tests. The oral administration of HEPm or of ISO significantly inhibited the neurogenic and inflammatory phases of formalin-induced pain, edema formation and local hyperemia, without causing any change to locomotor activity. Acute and repeated treatment of animals with HEPm reduced mechanical and thermal (heat and cold) hyperalgesia in the postoperative pain. In addition, administering HEPm or ISO markedly reduced nociceptive behavior induced by the peripheral and central injection of TRPV1 and TRPA1 channels activators. Finally, the antinociception provided by the administration of HEPm or ISO was reversed by the preadministration of naloxone.
  
  
  CONCLUSIONS
  Taken together, these results provide the first experimental evidence of the significant antinociceptive effect of HEPm and ISO in animal models of acute pain without causing sedation or locomotor dysfunction. This effect appears to be mediated, at least in part, by the activation of opioid receptors and/or by the inhibition of TRPV1 and TRPA1 channels. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant Polygala molluginifolia in the development of phytomedicines with analgesic properties.
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, SC 88040-900, Florianópolis, Brazil.
authors.forename: Catharina
authors.initials: C
authors.lastname: Nucci-Martins
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, SC 88040-900, Florianópolis, Brazil.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Nascimento
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Dalila
authors.initials: D
authors.lastname: Venzke
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Lizandra C
authors.initials: LC
authors.lastname: Brethanha
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Alysson V F
authors.initials: AV
authors.lastname: Sako
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Aldo S
authors.initials: AS
authors.lastname: Oliveira
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Inês M C
authors.initials: IM
authors.lastname: Brighente
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Micke
authors.affiliation: Department of Chemistry, Center of Physical and Mathematical Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil.
authors.forename: Moacir G
authors.initials: MG
authors.lastname: Pizzolatti
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC 88040-900, Brazil; Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, SC 88040-900, Florianópolis, Brazil. Electronic address: adair.santos@ufsc.br.
authors.forename: Adair R S
authors.initials: AR
authors.lastname: Santos
mesh_terms: D000700:Analgesics / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001938:Brazil; D004487:Edema / Q000188:drug therapy; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D007529:Isoflavones / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D031801:Polygala / Q000737:chemistry; D011957:Receptors, Opioid / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: C000611653:5,3',4'-trihydroxy-6',6'-dimethylpyrano(2',3':7,6)isoflavone; D000700:Analgesics; D007529:Isoflavones; D010936:Plant Extracts; D011957:Receptors, Opioid; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse
keywords: Opioid; Polygala molluginifolia; Polygalaceae; Postoperative pain; TRPA1; TRPV1