Kappa opioid receptor (KOR) signaling has been implicated in mediating behavioral and biochemical effects associated with
drug dependence. The most commonly used KOR antagonists,
norbinaltorphimine (norBNI) and (3R)-7-Hydroxy-N{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-
isoquinoline-carboxamide (JDTic), have provided a wealth of information in this area; however, the delayed onset and long-lasting effects of these antagonists complicate experimental design and interpretation of results, and make them less than ideal for clinical studies. Initial studies with the recently developed KOR antagonist,
LY2456302, show that the compound is a short acting, high-affinity, selective KOR antagonist with therapeutic potential for
mood disorders and
ethanol use in animal models, and is well tolerated in humans. The goal of the current study was to evaluate the effectiveness of
LY2456302 in alleviating the
nicotine withdrawal syndrome in mice. Mice were chronically treated with
nicotine for 14 days and physical and affective
nicotine withdrawal signs were measured using a spontaneous
nicotine withdrawal model and conditioned place aversion (CPA) following pre-treatment with
LY2456302, administered orally. Vehicle treated
nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs,
hyperalgesia, and CPA. Similar to previous studies with norBNI and JDTic,
LY2456302 alleviated the
nicotine withdrawal syndrome, as evidenced by decreased expression of
nicotine withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in
nicotine withdrawn mice following pre-treatment. Given the current results, and with its favorable pharmacokinetic and pharmacodynamic profile,
LY2456302 may be a useful therapeutic agent for treatment of multiple aspects of the
nicotine withdrawal syndrome.