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Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

Nature volume 398, pages 805–810 (1999)Cite this article

Abstract

Nicotine exerts antinociceptive effects by interacting with one or more of the subtypes of nicotinic acetylcholine receptors (nAChRs) that are present throughout the neuronal pathways that respond to pain1,2,3,4,5. To identify the particular subunits involved in this process, we generated mice lacking the α4 subunit of the neuronal nAChR by homologous recombination techniques and studied these together with previously generated mutant mice lacking the β2 nAChR subunit6. Here we show that the homozygous α4−/− mice no longer express high-affinity [3H]nicotine and [3H]epibatidine binding sites throughout the brain. In addition, both types of mutant mice display a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings further reveal that raphe magnus and thalamic neurons no longer respond to nicotine. The α4 nAChR subunit, possibly associated with the β2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception.

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Figure 1: Targeted mutagenesis and expression analysis of the α4 nAChR subunit.
Figure 2: Expression of neuronal nAChRs in mouse brain.
Figure 3: Antinociception of α4-knockout mice in the hot-plate and tail-flick assays.
Figure 4: Patch-clamp recordings of nicotine-evoked currents in raphe magnus, thalamus and dorsal horn of the spinal cord of α4+/+, α4−/− and β2−/− mice.

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Acknowledgements

The authors thank S. Brown and M. Picciotto for their contribution to this project; M.Zoli for scientific discussions; N. Bordes for help with experiments; and P. Parra, S. Edelstein and R.Klink for critical reading of the manuscript. This research was supported by grants from the Collège de France, the Association Francaise contre les Myopathies, Reynolds Pharm., EEC Biotech and Biomed Programs, the Council for Tobacco Research, the National Alliance for Research on Schizophrenia and Depression, and NIH (for M.I.D.).

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  1. Maria del Mar Arroyo-Jimenez

    Present address: Dept de Anatomia Humana, Agrupacion Medicina Enfermezia Humanidades, 02071, Albacete, Spain

Authors and Affiliations

  1. CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur, 28 rue du Dr Roux, Paris, Cdex 15, 75724, France

    Lisa M. Marubio, Maria del Mar Arroyo-Jimenez, Matilde Cordero-Erausquin, Clément Léna, Nicolas Le Novère, Alban de Kerchove d'Exaerde, Monique Huchet, M. Imad Damaj & Jean-Pierre Changeux

  2. Department of Pharmacology, Medical College of Virginia Commonwealth University, Richmond, 23298-0613, Virginia, USA

    M. Imad Damaj

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Marubio, L., Arroyo-Jimenez, M., Cordero-Erausquin, M. et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398, 805–810 (1999). https://doi.org/10.1038/19756

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