title: Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice.
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 Vehicle treated nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs, hyperalgesia, and CPA.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withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment.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.
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, 800 E. Leigh St., Suite 390A, Richmond, VA 23219, USA.
authors.forename: Kia J
authors.initials: KJ
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology/Toxicology, Virginia Commonwealth University, 1220 E. Broad St., MMRB, Box 980613, Richmond, VA 23219, USA.
authors.forename: Asti
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC, USA.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Department of Pharmacology/Toxicology, Virginia Commonwealth University, 1220 E. Broad St., MMRB, Box 980613, Richmond, VA 23219, USA. Electronic address: mdamaj@vcu.edu.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009538:Nicotine / Q000009:adverse effects / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D001549:Benzamides; D009292:Narcotic Antagonists; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009538:Nicotine; C000590915:Aticaprant
keywords: Kappa opioid receptor; Kappa opioid receptor antagonist; LY2456302; Nicotine dependence; Nicotine withdrawal