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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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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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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DOI: https://doi.org/10.1038/19756
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