RESUMEN
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.
Asunto(s)
Dolor , Receptores Nicotínicos/fisiología , Analgesia , Analgésicos no Narcóticos/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis , Neuronas/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Núcleos del Rafe/citología , Núcleos del Rafe/efectos de los fármacos , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Tálamo/citología , Tálamo/efectos de los fármacosRESUMEN
Nicotine affects many aspects of behaviour including learning and memory through its interaction with neuronal nicotinic acetylcholine receptors (nAChR). Functional nAChRs are pentameric proteins containing at least one type of alpha-subunit and one type of beta-subunit. The involvement of a particular neuronal nicotinic subunit in pharmacology and behaviour was examined using gene targeting to mutate beta 2, the most widely expressed nAChR subunit in the central nervous system. We report here that high-affinity binding sites for nicotine are absent from the brains of mice homozygous for the beta 2-subunit mutation. Further, electrophysiological recording from brain slices reveals that thalamic neurons from these mice do not respond to nicotine application. Finally, behavioural tests demonstrate that nicotine no longer augments the performance of beta 2-1- mice on passive avoidance, a test of associative memory. Paradoxically, mutant mice are able to perform better than their non-mutant siblings on this task.