title: Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test.
abstract: BACKGROUND
  The analgesic interaction between cannabinoids and local anesthetics has not been investigated. We sought to determine the nature of the interaction between the intrathecal cannabinoid receptor agonist (WIN 55,212-2) and bupivacaine using the formalin test.
  
  
  METHODS
  Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats. After intrathecal administration of WIN 55,212-2, bupivacaine, or their combination, 50 microL of 5% formalin was injected subcutaneously into the hindpaw. Dose-response curves were established and the respective ED50 (50% effective dose) values were determined for each agent alone. Fixed-ratio combinations of WIN 55,212-2 and bupivacaine were tested for combined antinociceptive effects in the formalin test and an isobolographic analysis was performed to characterize the pharmacologic interaction of both drugs.
  
  
  RESULTS
  Intrathecally administered WIN 55,212-2, bupivacaine, or their combination produced a dose-dependent decrease in the number of flinches during Phase 1 and 2 of the formalin test. Isobolographic analysis revealed a synergistic interaction between intrathecal WIN 55,212-2 and bupivacaine in both phases of the formalin test. In combination, the ED50 value was significantly smaller than the theoretical additive value (P < 0.05).
  
  
  CONCLUSIONS
  These results demonstrate that intrathecally coadministered WIN 55,212-2 and bupivacaine provide synergistic antinociceptive interaction in both phases of the formalin test.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Ewha Womans University Medical College, Seoul, Korea.
authors.forename: Sinyoung
authors.initials: S
authors.lastname: Kang
authors.forename: Chi Hyo
authors.initials: CH
authors.lastname: Kim
authors.forename: Heeseung
authors.initials: H
authors.lastname: Lee
authors.forename: Dong Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Jong In
authors.initials: JI
authors.lastname: Han
authors.forename: Rack Kyung
authors.initials: RK
authors.lastname: Chung
authors.forename: Guie Yong
authors.initials: GY
authors.lastname: Lee
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D048588:Benzoxazines; D002045:Bupivacaine / Q000008:administration & dosage*; D063386:Cannabinoid Receptor Agonists; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005557:Formaldehyde / Q000494:pharmacology*; D006801:Humans; D007278:Injections, Spinal / Q000379:methods; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D009281:Naphthalenes / Q000008:administration & dosage*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D000779:Anesthetics, Local; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D005557:Formaldehyde; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002045:Bupivacaine