title: Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding.
abstract: BACKGROUND
  Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies.
  
  
  OBJECTIVE
  This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen.
  
  
  METHODS
  Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays.
  
  
  RESULTS
  2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner.
  
  
  CONCLUSIONS
  Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA.
authors.forename: Justin N
authors.initials: JN
authors.lastname: Siemian
authors.affiliation: Department of Neurosurgery, Binzhou People's Hospital, Binzhou, Shandong Province, China.
authors.forename: Jiuzhou
authors.initials: J
authors.lastname: Li
authors.affiliation: Research Triangle Institute, Research Triangle Park, North Carolina, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA. junxuli@buffalo.edu.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000523:psychology; D001572:Benzofurans / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000187:drug effects*; D048288:Imidazolines / Q000494:pharmacology; D008024:Ligands; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule
chemical_list: D018712:Analgesics, Non-Narcotic; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D048288:Imidazolines; D008024:Ligands; C000605851:phenyzoline; D000082:Acetaminophen; C103723:2-(2-benzofuranyl)-2-imidazoline
keywords: Acetaminophen; Antinociception; Complete Freund’s adjuvant; Dose-addition analysis; Imidazoline I2 receptor; Rats