title: Enkephalin analog, cyclo[N(ε),N(β)-carbonyl-D-Lys(2),Dap(5)] enkephalinamide (cUENK6), inhibits the ethanol withdrawal-induced anxiety-like behavior in rats.
abstract: An analog of enkephalin, cyclo[N(ε),N(β)-carbonyl-D-Lys(2),Dap(5)] enkephalinamide (cUENK6), is predominantly a functional agonist of μ-opioid receptors (MOPr) and, to a lesser extent, of δ-opioid receptors (DOPr) in vitro. The aim of the present study was to determine whether cUENK6 could affect ethanol withdrawal-induced anxiety-like behavior in the elevated plus maze (EPM) test in rats. An anxiety-like effect of withdrawal was predicted to occur in the EPM test 24 h after the last ethanol administration (2 g/kg, intraperitoneally [i.p.]; 15% w/v once daily for 9 days). Ethanol withdrawal decreased the percent of time spent by rats in the open arms and the percent of open-arms entries. cUENK6 (0.25 nmol), given by intracerebroventricular (i.c.v.) injection, significantly reversed these anxiety-like effects of ethanol withdrawal and elevated the percent of time spent by rats in the open arms and the percent of open-arms entries. These effects of cUENK6 were significantly inhibited by the DOPr antagonist naltrindole (NTI) (5 nmol, i.c.v.), but not by the MOPr antagonist β-funaltrexamine (β-FNA) (5 nmol, i.c.v.). The preferential DOPr agonist [Leu(5)]-enkephalin (LeuEnk) (2.7 and 5.4 nmol, i.c.v.) and the MOPr agonist morphine (6.5 and 13 nmol, i.c.v.) reduced the anxiety-like effects of ethanol withdrawal. cUENK6 at the dose of 0.25 nmol did not disturb locomotor activity in the EPM, in contrast to cUENK6 at the dose of 0.5 nmol, and morphine at 6.5 and 13 nmol. However, similarly to LeuEnk, cUENK6 induced the anxiolytic-like effects in naïve rats. Thus, our study suggests that cUENK6 reduced ethanol withdrawal-induced anxiety-like behavior by activation of δ-opioid receptors rather than μ-opioid receptors.
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland. Electronic address: ewa.gibulabruzda@umlub.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gibula-Bruzda
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Marszalek-Grabska
authors.affiliation: Laboratory of Peptides, Department of Chemistry, University of Warsaw, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Witkowska
authors.affiliation: Laboratory of Peptides, Department of Chemistry, University of Warsaw, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Izdebski
authors.affiliation: Department of Pharmacology and Pharmacodynamics, Medical University, Chodzki 4A, 20-093 Lublin, Poland.
authors.forename: Jolanta H
authors.initials: JH
authors.lastname: Kotlinska
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D004743:Enkephalin, Leucine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology*; D000431:Ethanol / Q000009:adverse effects*; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000523:psychology*
chemical_list: D000701:Analgesics, Opioid; D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D004745:Enkephalins; D009292:Narcotic Antagonists; D018377:Neurotransmitter Agents; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C543922:enkephalinamide, cyclo(Nepsilon,Nbeta-carbonyl-Lys(2)-Dap(5))-; D000431:Ethanol; D004743:Enkephalin, Leucine; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; C055382:naltrindole
keywords: Anxiety; Enkephalin analogs; Ethanol withdrawal; Mice; Morphine