title: 6-Methoxyflavanone attenuates mechanical allodynia and vulvodynia in the streptozotocin-induced diabetic neuropathic pain.
abstract: BACKGROUND
  Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities.
  
  
  OBJECTIVE
  Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAAreceptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain.
  
  
  METHODS
  6-MeOF was evaluated for analgesic effect in the hot plate test and streptozotocin-induced diabetic neuropathic pain in female rats using von Frey hairs. The possible involvement of opioidergic and GABAergic mechanisms was investigated using naloxone and pentylenetetrazole (PTZ) antagonists, respectively. The biodistribution of 6-MeOF in plasma and CNS was examined using a validated HPLC/UV analytical method. The binding affinity of 6-MeOF with opioid and GABA receptors was studied using molecular docking simulation approach.
  
  
  RESULTS
  6-MeOF (10 and 30mg/kg) attenuated the acute phasic thermal nociception in the hot plate test while in the case of streptozotocin-induced diabetic neuropathy model, 6-MeOF (10 and 30mg/kg) produced static/dynamic anti-allodynic (increased paw withdrawal threshold and latency) as well as static/dynamic anti-vulvodynic effects (increased flinching response threshold and latency), when compared to the vehicle and standard gabapentin (75mg/kg). In silico studies depicted the preference of 6-MeOF for the delta- and kappa-opioid and GABAAreceptors. Moreover, the pharmacokinetic profile revealed a quick appearance of 6-MeOF in the systemic circulation and brain areas with maximum concentration observed after 30min in the amygdala, brain stem and cerebral cortex.
  
  
  CONCLUSIONS
  6-MeOF readily crosses the blood brain barrier and may be effective in attenuating the diabetes-induced allodynia as well as vulvodynia, probably through interactions with the GABAergic and opioidergic systems.
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: naina.akbar@yahoo.com.
authors.forename: Shehla
authors.initials: S
authors.lastname: Akbar
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fazal_subhan@upesh.edu.pk.
authors.forename: Fazal
authors.initials: F
authors.lastname: Subhan
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, Pakistan. Electronic address: nasiara.karim@hotmail.com.
authors.forename: Nasiara
authors.initials: N
authors.lastname: Karim
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: shahidsalim_2002@hotmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: nisarahmadsatal@yahoo.com.
authors.forename: Nisar
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: gohar.pharmacist@gmail.com.
authors.forename: Gowhar
authors.initials: G
authors.lastname: Ali
authors.affiliation: Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan. Electronic address: wmahmood@cit.net.pk.
authors.forename: Wajahat
authors.initials: W
authors.lastname: Mahmood
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address: fawad.khwaja@yahoo.com.
authors.forename: Khwaja
authors.initials: K
authors.lastname: Fawad
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003198:Computer Simulation; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D044950:Flavanones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077206:Gabapentin; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008958:Models, Molecular; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D059225:Nociception / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D013311:Streptozocin; D023382:Toxicity Tests, Acute; D056650:Vulvodynia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000598908:6-methoxyflavanone; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D044950:Flavanones; D018079:Receptors, GABA; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D013311:Streptozocin; D000077206:Gabapentin; D010433:Pentylenetetrazole
keywords: Diabetes mellitus; Flavonoids; GABA receptors; Neuropathy; Opioid receptors; Pharmacokinetics