Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

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 and Jean-Pierre Changeux
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Lisa M. Marubio: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Maria del Mar Arroyo-Jimenez: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Matilde Cordero-Erausquin: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Clément Léna: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Nicolas Le Novère: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Alban de Kerchove d'Exaerde: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Monique Huchet: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
M. Imad Damaj: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur
Jean-Pierre Changeux: CNRS UA D1284-Neurobiologie Molculaire, Institut Pasteur

Nature, 1999, vol. 398, issue 6730, 805-810

Abstract: 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.

Date: 1999
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DOI: 10.1038/19756

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