title: Correlation of rat cortical Fas-associated death domain (FADD) protein phosphorylation with the severity of spontaneous morphine abstinence syndrome: role of α(2)-adrenoceptors and extracellular signal-regulated kinases.
abstract: Fas-associated death domain (FADD) phosphorylation was recently implicated in opiate-induced neuroplasticity. To further explore the role of FADD in the mechanisms of morphine-induced physical dependence, the regulation of cortical p-FADD (and their interactions with α(2)-adrenoceptors and other signalling pathways) was assessed during spontaneous opiate withdrawal (SW) in morphine-dependent rats (10-100 mg/kg for 6 days). The main results indicated that oligomeric p-FADD in the cerebral cortex mirrored the time course of morphine SW (12-96 h), which resulted in a striking correlation between p-FADD and the intensity (behavioural scores) of morphine abstinence (Spearman correlation coefficient: 0.59, n = 39, p < 0.0001). The inactivation of brain α(2)-adrenoceptors (EEDQ at SW 12 h) further enhanced morphine abstinence intensity and cortical p-FADD content at SW 24 h. The disruption of ERK1/2 signalling (SL 327 at SW 4 h and SW 8 h) did not alter morphine abstinence at SW 12 h, but it attenuated the behavioural syndrome at SW 24 h. This inhibition of ERK1/2, however, did not prevent the up-regulation of oligomeric p-FADD at SW 12 h and 24 h. These data indicate that cortical oligomeric p-FADD, mainly through an interaction with inhibitory α(2)-adrenoceptors, plays a functional role in the behavioural expression of morphine abstinence in rats.
authors.affiliation: Laboratori de Neurofarmacologia, IUNICS, Universitat de les Illes Balears, Palma de Mallorca, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramos-Miguel
authors.forename: Antonio
authors.initials: A
authors.lastname: Miralles
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002540:Cerebral Cortex / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D009021:Morphine Dependence / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; C490443:Pea15 protein, rat; D010750:Phosphoproteins; D018341:Receptors, Adrenergic, alpha-2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases