It has been shown previously that the endogenous opioid system may be involved in the behavioral effects of nicotine. In the present study, the participation of endogenous enkephalins on nicotine responses has been investigated by using preproenkephalin knock-out mice. Acute nicotine-induced hypolocomotion remained unaffected in these mice. In contrast, antinociception elicited in the tail-immersion and hot-plate tests by acute nicotine administration was reduced in mutant animals. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine induced a conditioned place preference in wild-type animals, but this effect was absent in knock-out mice. Accordingly, in vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels in the nucleus accumbens induced by nicotine was also reduced in preproenkephalin-deficient mice. Finally, the somatic expression of the nicotine withdrawal syndrome precipitated in nicotine-dependent mice by mecamylamine was significantly attenuated in mutant animals. In summary, the present results indicate that endogenous opioid peptides derived from preproenkephalin are involved in the antinociceptive and rewarding properties of nicotine and participate in the expression of physical nicotine dependence.

This work was supported by National Institute on Drug Abuse–National Institutes of Health Grant/n1RO1DA016768, the Human Frontier Science Program Organization (RG0077/2000-B), Generalitat de Catalunya (Distinción de la Generalitat and 2002SGR00193), and Fondo de Investigación Sanitario (FIS) Grants 03/0305, G03/005, and C03/06. P.R. was supported by an FIS investigator contract. V.M. is a postdoctoral fellow supported by Fundación Carolina. F.B. is a researcher supported by the Ramón y Cajal Program of Ministerio de Ciencia y Tecnología