Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

• Published in: The Journal of neuroscience 2005-02, Vol.25 (5), p.1103-1112
• Main Authors: Berrendero, Fernando, Mendizabal, Victoria, Robledo, Patricia, Galeote, Lola, Bilkei-Gorzo, Andras, Zimmer, Andreas, Maldonado, Rafael
• Format: Article
• Language: English
• Subjects: Addicció; Analgesics - pharmacology; Analgesics - toxicity; Animals; Antinociception; Behavioral/Systems/Cognitive; Conditioning, Classical; Dependence; Dopamine - analysis; Efectes fisiològics; Enkephalin; Enkephalins - deficiency; Enkephalins - genetics; Enkephalins - physiology; Female; Hot Temperature; Knock-out mice; Male; Mecamylamine - toxicity; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Motor Activity - drug effects; Motor Activity - physiology; Nicotina; Nicotine; Nicotine - pharmacology; Nicotine - toxicity; Nucleus Accumbens - chemistry; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiopathology; Opioid Peptides - biosynthesis; Opioid Peptides - deficiency; Opioid Peptides - physiology; Pain Measurement; Pain Threshold - drug effects; Pain Threshold - physiology; Protein Precursors - deficiency; Protein Precursors - genetics; Protein Precursors - physiology; Receptors nicotínics; Reward; Spatial Behavior - drug effects; Spatial Behavior - physiology; Substance Withdrawal Syndrome - etiology; Substance Withdrawal Syndrome - genetics; Substance Withdrawal Syndrome - physiopathology; Tobacco Use Disorder - genetics; Tobacco Use Disorder - physiopathology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3008-04.2005

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.