Pr Jean-Pierre CHANGEUX and his team from the Molecular Neurobiology Unit of the Institut Pasteur* in Paris, have demonstrated for the first time the critical role of a particular type of a nicotinic receptor in the analgesic effects of nicotine. This work is of importance because it opens new ways for the development of new analgesic agents devoid of opioïds side effects. These results are published in "Nature".
Nicotine exerts analgesic effects by interacting with one or more of the subtypes of nicotinic acetylcholine receptors present in the brain. However,the involvement of a particular subunit in nicotine analgesia has been difficult to assess. Previous work had suggested the possible contribution of the widely-expressed neuronal alpha-4 and beta-2 subunits.
In order to demonstrate this hypothesis, researchers at the Institut Pasteur, have generated two lines of mutant mice that lack either the neuronal alpha-4 or beta-2 subunit. Mutant mice no longer have an analgesic response to nicotine and epibatidine (an analgesic compound close to nicotine) in certain tests. However, they still exhibit an analgesic response to morphine, indicating that these two classes of analgesics act through different pathways. More importantly, these experiments demonstrate the role of the alpha-4 and beta-2 subunits in mediating the analgesic effects of nicotine.
In brain areas that play an important role in the nicotinic analgesic pathways, such as the thalamus and raphe magnus, mutant mice display a loss of high affinity nicotine and epibatidine binding sites. In addition, recordings from neurons in these areas have demonstrated a loss of response to nicotine in mutant mice, suggesting that alpha-4 and beta-2 subunits are necessary for the formation of functional receptors in areas implicated in nicotine analgesia.
Other experiments suggest that subunits, other than alpha-4 and beta-2, are involved in the analgesic effects of nicotine. When measuring a peripheral reflex, mutant mice that lack alpha-4 subunit display a much diminished sensitivity to nicotine.These data indicate a contribution of peripheral non alpha-4 receptors.
In conclusion, these results demonstrate that the alpha-4 and beta-2 subunits play a critical, though not exclusive, role in the analgesic effects of nicotine. Pr Jean-Pierre CHANGEUX's team has undertaken to characterise other receptors involved. Pharmacological compounds which target these receptors may constitute new treatments for pain that are devoid of opiate side effects.
*Institut Pasteur Unit Associated with the CNRS UA D1284
1- " Reduced antinociception in mice lacking neuronal nicotinic
receptor subunits". Nature, April 29, 1999.
Lisa M. Marubio*, Maria del Mar Arroyo-Jimenez*, Mathilde Cordero-Erausquin*, Clément Léna*, Nicolas Le Novère*, Alban de Kerchove d'Exaerde*, Monique Huchet*, M. Imad Damaj§ and Jean-Pierre Changeux*.
* Molecular Neurobiology Unit, Institut Pasteur - CNRS UA D1284, Paris,
§ Dept of Pharmacology, Medical College of Virginia of Virginia Commonwealth University, Richmond, USA.
- Jean-Pierre CHANGEUX, Tél : 33 1 45 68 88 05
- Lisa MARUBIO, Tél : 33 1 45 68 88 06