Adaptation in 5-HT2 receptors-CaMKII signaling in lateral habenula underlies increased nociceptive-sensitivity in ethanol-withdrawn rats.

摘要: Abstract Alcoholics often experience hyperalgesia, especially during abstinence, yet the underlying cellular and molecular bases are unclear. Recent evidence suggests that 5-HT type 2 receptors (5-HT2Rs) at glutamatergic synapses on lateral habenula (LHb) neurons may play a critical role. We, therefore, measured paw withdrawal responses to thermal mechanical stimuli, alcohol intake in rat model of intermittent drinking paradigm, as well spontaneous transmission (sEPSCs), firing LHb brain slices. Here, we report nociceptive sensitivity was higher rats 24 h from chronic consumption than alcohol-naive counterparts. The basal frequency sEPSCs firings slices withdrawn Naive rats, 5-HT2R antagonists attenuated enhancement. Also, an acute ethanol-induced increase smaller rats; it by but mimicked agonists. Importantly, intra-LHb infusion agonists increased while or reuptake blocker decreased rats. Additionally, KN-62, CaMKII inhibitor, enhancement EPSCs induced agonist. Furthermore, KN-62 reduced intake. Quantitative real-time PCR assay detected mRNA 5-HT2A 2C LHb. Thus adaptation 5-HT2R-CaMKII signaling pathway contributes hyper-glutamatergic state, hyperactivity consumption.