Inflammatory pain in the rabbit: a new, efficient method for measuring mechanical hyperalgesia in the hind paw

J Neurosci Methods. 2008 Feb 15;168(1):76-87. doi: 10.1016/j.jneumeth.2007.09.028. Epub 2007 Oct 3.

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.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Bradykinin / administration & dosage
  • Bradykinin / analogs & derivatives
  • Carrageenan
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ethers / blood
  • Hydrocarbons, Fluorinated / blood
  • Hyperalgesia / etiology*
  • Hyperalgesia / pathology*
  • Hyperalgesia / prevention & control
  • Indomethacin / administration & dosage
  • Inflammation / chemically induced
  • Inflammation / complications
  • Kallidin / administration & dosage
  • Kallidin / analogs & derivatives
  • Metacarpus / drug effects
  • Metacarpus / physiopathology*
  • Pain / complications*
  • Pain / etiology
  • Pain Measurement / instrumentation
  • Pain Measurement / methods*
  • Pain Threshold / drug effects
  • Rabbits
  • Reaction Time / drug effects
  • Spectrum Analysis
  • Time Factors

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Ethers
  • Hydrocarbons, Fluorinated
  • bradykinin, Lys-Leu(8)-desArg(9)-
  • Kallidin
  • fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether
  • icatibant
  • Carrageenan
  • Bradykinin
  • Indomethacin