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.

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.