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

Abstract

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 tailimmersion 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.

Presynaptic Opioid and Nicotinic Receptor Modulation of Dopamine Overflow in the Nucleus Accumbens

“…Both -opioids and nicotine are considered addictive drugs that are readily self-administered by rats and humans (Thompson and Pickens, 1970;Goldberg and Henningfield, 1988). They also both have analgesic properties when applied directly to the NAc (Schmidt et al, 2001;Berrendero et al, 2005). Importantly, changes in NAc shell DA levels have been associated with each of these phenomena (Di Chiara and Imperato, 1988;Schmidt et al, 2001;Berrendero et al, 2005).…”

“…They also both have analgesic properties when applied directly to the NAc (Schmidt et al, 2001;Berrendero et al, 2005). Importantly, changes in NAc shell DA levels have been associated with each of these phenomena (Di Chiara and Imperato, 1988;Schmidt et al, 2001;Berrendero et al, 2005). In fact, whether taken systemically or microinjected focally into either the VTA or NAc, these drugs raise extracellular NAc DA levels as measured by microdialysis (Devine et al, 1993;Hemby et al, 1995;Ferrari et al, 2002;Hirose et al, 2005).…”

Nicotine Effects and the Endogenous Opioid System

“…Systemic administration of NIC suppresses nociceptive pain elicited by thermal and mechanical noxious stimuli in rodents, as assessed with the tail-flick test (14), tail-immersion test (15,16), hot-plate test (14,15,17), and tail pinch test (13,18). Microinjection of an nAChR agonist (ABT-594) into the nucleus raphe magnus (19) and intrathecal administration of NIC (13) showed antinociceptive effects by the hot plate test and tail pinch test, respectively.…”

Overview of the pharmacogenomics of cigarette smoking

“…149 The opiate system is important for the rewarding properties of nicotine and may be involved in drug craving. [150][151][152][153] Acute nicotine administration results in release of endogenous b-endorphins 154 that activate the m-opioid receptor, and the A118G polymorphism (Asn404Asp) in OPRM1 decreases binding affinity for b-endorphins. 155,156 OPRM1 is located in chromosome 6q24-q25 and this region was recently linked to FTND scores and withdrawal severity (Table 1).…”