Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

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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.