title: Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone.
abstract: BACKGROUND
  Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy.
  
  
  OBJECTIVE
  This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats.
  
  
  METHODS
  Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule-controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs.
  
  
  RESULTS
  Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.), and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations.
  
  
  CONCLUSIONS
  Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Thorn
authors.forename: Justin N
authors.initials: JN
authors.lastname: Siemian
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000378:metabolism*; D048288:Imidazolines / Q000494:pharmacology*; D007249:Inflammation; D008024:Ligands; D008297:Male; D059225:Nociception / Q000187:drug effects*; D010098:Oxycodone / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000276:immunology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D048288:Imidazolines; D008024:Ligands; C487767:imidazoline receptor 2; C000605851:phenyzoline; C103723:2-(2-benzofuranyl)-2-imidazoline; D010098:Oxycodone