title: Reduced antinociception in mice lacking neuronal nicotinic receptor subunits.
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 pain. To identify the particular subunits involved in this process, we generated mice lacking the alpha4 subunit of the neuronal nAChR by homologous recombination techniques and studied these together with previously generated mutant mice lacking the beta2 nAChR subunit. Here we show that the homozygous alpha4-/- 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 alpha4 nAChR subunit, possibly associated with the beta2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception.
authors.affiliation: CNRS UA D1284-Neurobiologie Moléculaire, Institut Pasteur, Paris, France.
authors.forename: L M
authors.initials: LM
authors.lastname: Marubio
authors.forename: M
authors.initials: M
authors.lastname: del Mar Arroyo-Jimenez
authors.forename: M
authors.initials: M
authors.lastname: Cordero-Erausquin
authors.forename: C
authors.initials: C
authors.lastname: Léna
authors.forename: N
authors.initials: N
authors.lastname: Le Novère
authors.forename: A
authors.initials: A
authors.lastname: de Kerchove d'Exaerde
authors.forename: M
authors.initials: M
authors.lastname: Huchet
authors.forename: M I
authors.initials: MI
authors.lastname: Damaj
authors.forename: J P
authors.initials: JP
authors.lastname: Changeux
mesh_terms: D000698:Analgesia; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D009474:Neurons / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010146:Pain; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013788:Thalamus / Q000166:cytology / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine