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. 2015 Oct:97:270-4.
doi: 10.1016/j.neuropharm.2015.05.023. Epub 2015 Jun 1.

Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice

Kia J Jackson  1 , Asti Jackson  2 , F Ivy Carroll  3 , M Imad Damaj  4
Affiliations

Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice

Kia J Jackson et al. Neuropharmacology. 2015 Oct.

Abstract

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 Vehicle treated nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs, hyperalgesia, and CPA.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withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment.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.

Keywords: Kappa opioid receptor; Kappa opioid receptor antagonist; LY2456302; Nicotine dependence; Nicotine withdrawal.

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Conflict of interest statement

There are no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. LY2456302 attenuates physical and affective nicotine withdrawal signs in mice
Withdrawal from nicotine induced a A) significant increase in anxiety- related behavior, B) significant increase in somatic signs, and C) a significant decrease in hot plate latency. Compared to vehicle, pretreatment with LY2456302 A) significantly decreased expression of anxiety-related behavior at 3 and 10 mg/kg p.o., B) significantly reduced somatic signs at all doses tested, and C) significantly increased hot plate latency at 3 and 10 mg/kg p.o. in nicotine withdrawal mice. Each point represents the mean ± S.E.M. of 7–8 mice per group. All doses are expressed in mg/kg. * denotes p< 0.05 vs. Sal/Veh group, # denotes p< 0.05 vs. Nic/Veh group. Veh, vehicle; Sal, saline; Nic, nicotine; LY, LY2456302
Figure 2
Figure 2. LY2456302 blocks expression of nicotine withdrawal aversion
Mecamylamine (3.5 mg/kg, s.c.) precipitated a significant nicotine withdrawal CPA in chronic nicotine-infused mice. Pretreatment with LY2456302 dose-dependently blocked expression of CPA. Each point represents the mean ± S.E.M. of 7–8 mice per group. * denotes p< 0.05 vs. Sal-Mec/Veh control group, # denotes p< 0.05 vs. Nic-Mec/Veh. Veh, vehicle; Mec, mecamylamine; Sal, saline; Nic, nicotine; LY, LY2456302
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