Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

• Published in: Nature (London) 1999-04, Vol.398 (6730), p.805-810
• Main Authors: Changeux, Jean-Pierre, Marubio, Lisa M, Arroyo-Jimenez, Maria del Mar, Cordero-Erausquin, Matilde, Léna, Clément, Novère, Nicolas Le, d'Exaerde, Alban de Kerchove, Huchet, Monique, Damaj, M. Imad
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics, Non-Narcotic - pharmacology; Animals; Biological and medical sciences; Biology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; letter; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Mutagenesis; Mutation; Neurology; Neurons; Neurons - physiology; Nicotine; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Pain; Pyridines - pharmacology; Raphe Nuclei - cytology; Raphe Nuclei - drug effects; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - genetics; Receptors, Nicotinic - physiology; Rodents; Science; Science (multidisciplinary); Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Spinal Cord - cytology; Spinal Cord - drug effects; Thalamus - cytology; Thalamus - drug effects; Vertebrates: nervous system and sense organs
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/19756

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 pain. 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 subunit. 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.