title: Docking, characterization and investigation of β-cyclodextrin complexed with citronellal, a monoterpene present in the essential oil of Cymbopogon species, as an anti-hyperalgesic agent in chronic muscle pain model.
abstract: BACKGROUND
  Citronellal (CT) is a monoterpene with antinociceptive acute effect. β-Cyclodextrin (βCD) has enhanced the analgesic effect of various substances.
  
  
  OBJECTIVE
  To evaluate the effect of CT both complexed in β-cyclodextrin (CT-βCD) and non-complexed, in a chronic muscle pain model (CMP) in mice.
  
  
  METHODS
  The complex containing CT in βCD was obtained and characterized in the laboratory. The anti-hyperalgesic effect of CT and CT-βCD was evaluated in a pre-clinical in vivo study in a murine CMP.
  
  
  METHODS
  The complex was characterized through differential scanning calorimetry, derivative thermogravimetry, moisture determination, infrared spectroscopy and scanning electron microscopy. Male Swiss mice were pre-treated with CT (50mg/kg, po), CT-βCD (50mg/kg, po), vehicle (isotonic saline, po) or standard drug (tramadol4 mg/kg, ip). 60 min after the treatment and then each 1h, the mechanic hyperalgesia was evaluated to obtain the time effect. In addition, the muscle strength using grip strength meter and hyperalgesia were also performed daily, for 7 days. We assessed by immunofluorescence for Fos protein on brains and spinal cords of mice. The involvement of the CT with the glutamatergic system was studied with molecular docking.
  
  
  RESULTS
  All characterization methods showed the CT-βCD complexation. CT-induced anti-hyperalgesic effect lasted until 6h (p <0.001) while CT-βCD lasted until 8h (p <0.001vs vehicle and p <0.001vs CT from the 6th h). CT-βCD reduced mechanical hyperalgesia on all days of treatment (p <0.05), without changing muscle strength. Periaqueductal gray (p <0.01) and rostroventromedular area (p <0.05) showed significant increase in the Fos protein expression while in the spinal cord, there was a reduction (p <0.001). CT showed favorable energy binding (-5.6 and -6.1) to GluR2-S1S2J protein based in the docking score function.
  
  
  CONCLUSIONS
  We can suggest that βCD improved the anti-hyperalgesic effect of CT, and that effect seems to involve the descending pain-inhibitory mechanisms, with a possible interaction of the glutamate receptors, which are considered as promising molecules for the management of chronic pain such as CMP.
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Priscila L
authors.initials: PL
authors.lastname: Santos
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Renan G
authors.initials: RG
authors.lastname: Brito
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Marlange A
authors.initials: MA
authors.lastname: Oliveira
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Jullyana S S
authors.initials: JS
authors.lastname: Quintans
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Adriana G
authors.initials: AG
authors.lastname: Guimarães
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Márcio R V
authors.initials: MR
authors.lastname: Santos
authors.affiliation: Department of Pharmacy, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Paula P
authors.initials: PP
authors.lastname: Menezes
authors.affiliation: Department of Pharmacy, Federal University of Sergipe, São Cristóvão, SE, Brazil.
authors.forename: Mairim R
authors.initials: MR
authors.lastname: Serafini
authors.affiliation: Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil.
authors.forename: Irwin R A
authors.initials: IR
authors.lastname: Menezes
authors.affiliation: Department of Biological Chemistry, Regional University of Cariri, Crato, CE, Brazil.
authors.forename: Henrique D M
authors.initials: HD
authors.lastname: Coutinho
authors.affiliation: Department of Pharmacy, Federal University of Sergipe, São Cristóvão, SE, Brazil.. Electronic address: adriasa2001@yahoo.com.br.
authors.forename: Adriano A S
authors.initials: AA
authors.lastname: Araújo
authors.affiliation: Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.. Electronic address: lucindojr@gmail.com.
authors.forename: Lucindo J
authors.initials: LJ
authors.lastname: Quintans-Júnior
mesh_terms: D000080462:Acyclic Monoterpenes; D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D059350:Chronic Pain / Q000517:prevention & control*; D031743:Cymbopogon / Q000737:chemistry*; D018737:Hand Strength; D006930:Hyperalgesia / Q000517:prevention & control*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D039821:Monoterpenes / Q000737:chemistry* / Q000494:pharmacology*; D053580:Muscle Strength / Q000187:drug effects; D063806:Myalgia / Q000517:prevention & control*; D009822:Oils, Volatile / Q000737:chemistry* / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000080462:Acyclic Monoterpenes; D000447:Aldehydes; D000700:Analgesics; D039821:Monoterpenes; D009822:Oils, Volatile; D047392:beta-Cyclodextrins; C108217:citronellal
keywords: Chronic pain; Citronellal; Cyclodextrin; Fibromyalgia; Monoterpene; c-Fos