Adaptation in 5-HT2 receptors-CaMKII signaling in lateral habenula underlies increased nociceptive-sensitivity in ethanol-withdrawn rats. (1st November 2019)

• Record Type: Journal Article
• Authors: Zuo, Wanhong; Wu, Liangzhi; Mei, Qinghua; Zuo, Qikang; Zhou, Zhongyang; Fu, Rao; Li, Wenting; Wu, Wei; Matthew, Leberer; Ye, Jiang-Hong
• Is Part Of: Neuropharmacology. Volume 158(2019)
• Publication Date: 2019-11-01
• Subjects: Alcohol withdrawal -- Serotonin -- Glutamatergic transmission -- Electrophysiology -- Behavioral; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107747
• Languages: English
• ISSNs: 0028-3908

Abstract

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-HT2 Rs) at glutamatergic synapses on lateral habenula (LHb) neurons may play a critical role. We, therefore, measured paw withdrawal responses to thermal and mechanical stimuli, and alcohol intake in a rat model of intermittent drinking paradigm, as well as spontaneous glutamatergic transmission (sEPSCs), and firing of LHb neurons in brain slices. Here, we report that nociceptive sensitivity was higher in rats at 24 h withdrawal from chronic alcohol consumption than that of alcohol-naive counterparts. The basal frequency of sEPSCs and firings was higher in slices of withdrawn rats than that of Naïve rats, and 5-HT2R antagonists attenuated the enhancement. Also, an acute ethanol-induced increase of sEPSCs and firings was smaller in withdrawal than in Naïve rats; it was attenuated by 5-HT2 R antagonists but mimicked by 5-HT2 R agonists. Importantly, intra-LHb infusion of 5-HT2 R agonists increased nociceptive sensitivity in Naïve rats, while antagonists or 5-HT reuptake blocker decreased nociceptive sensitivity and alcohol intake in withdrawn rats. Additionally, KN-62, a CaMKII inhibitor, attenuated the enhancement of EPSCs and firing induced by acute alcohol and by 5-HT2 R agonist. Furthermore, intra-LHb KN-62 reduced nociceptive sensitivity and alcohol intake. Quantitative real-time PCR assay detected mRNA of 5-HT2A and 2C in the LHb. Thus adaptation in 5-HT2 R-CaMKII signaling pathway contributes to the hyper-glutamatergic state, the hyperactivity of LHb neurons as well as the higher nociceptive sensitivity in rats withdrawn from chronic alcohol consumption. Highlights: Alcohol-withdrawn rats show higher sensitivity to thermal and mechanical stimuli. Intra-LHb infusion of 5-HT2 R agonists increases nociception in alcohol-naïve rats. Intra-LHb 5-HT2 R antagonists decreases nociception in alcohol-withdrawn rats. KN-62 suppresses sEPSCs and firing of LHb neurons induced by acute alcohol. Intra-LHb KN-62 reduces nociceptive sensitivity and alcohol intake.