Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice

Neuropharmacology. 2016 Mar;102:236-43. doi: 10.1016/j.neuropharm.2015.11.024. Epub 2015 Nov 27.


Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid-induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.

Keywords: Acetic acid; Analgesics; Conditioned place aversion; Mice; Pain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Avoidance Learning / drug effects*
  • Avoidance Learning / physiology
  • Behavior, Animal / drug effects
  • Ketoprofen / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Morphine / pharmacology*
  • Piperidines / pharmacology
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Receptors, Opioid, mu / agonists
  • Tetrahydroisoquinolines / pharmacology
  • Visceral Pain / physiopathology*


  • 7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide
  • Analgesics, Opioid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Piperidines
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Tetrahydroisoquinolines
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Morphine
  • Ketoprofen