title: Inflammatory pain in the rabbit: a new, efficient method for measuring mechanical hyperalgesia in the hind paw.
abstract: The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500-700 g), baseline hind paw withdrawal thresholds typically fell within the 60-80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 microL, intra-plantar), withdrawal thresholds dropped by approximately 30-40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED50=2.56 mg/kg, p.o.) or the bradykinin B2 receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED50=0.096 mg/kg, s.c.) or the bradykinin B1 receptor peptide antagonist [des-Arg10, Leu9]-kallidin (ED50=0.45 mg/kg, s.c.). Rabbits treated with the novel B(1) receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED50=20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic-pharmacodynamic (PK-PD) relationships (compound A plasma EC50=402.6 nM). We conclude that the Electrovonfrey method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, MS 29-2-B, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Dong
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Ella
authors.initials: E
authors.lastname: Magal
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Gondi N
authors.initials: GN
authors.lastname: Kumar
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Johnson
authors.forename: Barton H
authors.initials: BH
authors.lastname: Manning
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004987:Ethers / Q000097:blood; D006845:Hydrocarbons, Fluorinated / Q000097:blood; D006930:Hyperalgesia / Q000209:etiology* / Q000473:pathology* / Q000517:prevention & control; D007213:Indomethacin / Q000008:administration & dosage; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D007609:Kallidin / Q000008:administration & dosage / Q000031:analogs & derivatives; D008663:Metacarpus / Q000187:drug effects / Q000503:physiopathology*; D010146:Pain / Q000150:complications* / Q000209:etiology; D010147:Pain Measurement / Q000295:instrumentation / Q000379:methods*; D017288:Pain Threshold / Q000187:drug effects; D011817:Rabbits; D011930:Reaction Time / Q000187:drug effects; D013057:Spectrum Analysis; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; C082229:bradykinin, Lys-Leu(8)-desArg(9)-; D007609:Kallidin; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; C065679:icatibant; D002351:Carrageenan; D001920:Bradykinin; D007213:Indomethacin