View the Current Issue

Article

  • The EMBO Journal (1998) 17, 886 - 897
  • doi:10.1093/emboj/17.4.886

Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal

Frédéric Simonin1, Olga Valverde2, Claire Smadja2, Susan Slowe3, Ian Kitchen3, Andrée Dierich4, Marianne Le Meur4, Bernard P. Roques2, Rafael Maldonado2 and Brigitte L. Kieffer1

  1. UPR 9050 CNRS, ESBS Université Louis Pasteur, 67400 Illkirch, Strasbourg France
  2. Département de Pharmacochimie Moléculaire et Structurale, INSERM U266. URA D1500 CNRS, Université René Descartes, 75270 Paris Cedex, France
  3. Receptors and Cellular Regulation Research Group, School of Biological Sciences, University of Surrey, Guildford, Surrey GU2 5XH, UK
  4. Institut de Génétique et Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, Strasbourg, France

Correspondence to:

Brigitte L. Kieffer, E-mail: briki@esbs.u-strasbg.fr

Received 29 September 1997; Accepted 3 December 1997; Revised 3 December 1997

mu-, delta- and kappa-opioid receptors are widely expressed in the central nervous system where they mediate the strong analgesic and mood-altering actions of opioids, and modulate numerous endogenous functions. To investigate the contribution of the kappa-opioid receptor (KOR) to opioid function in vivo, we have generated KOR-deficient mice by gene targeting. We show that absence of KOR does not modify expression of the other components of the opioid system, and behavioural tests indicate that spontaneous activity is not altered in mutant mice. The analysis of responses to various nociceptive stimuli suggests that the KOR gene product is implicated in the perception of visceral chemical pain. We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic kappa-agonist U-50,488H. Finally, our results indicate that this receptor does not contribute to morphine analgesia and reward, but participates in the expression of morphine abstinence. Together, our data demonstrate that the KOR-encoded receptor plays a modulatory role in specific aspects of opioid function.

  • Keywords:

    • nociception,
    • opioid pharmacology,
    • kappa-opioid receptor knock-out,
    • spontaneous behaviour