NeuropharmacologyAug 26, 2019

Changes in serotonin receptor signaling in the brain's emotion area linked to higher pain sensitivity after alcohol withdrawal in rats

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

Nociceptive sensitivity was higher in rats 24 hours after withdrawal from chronic alcohol consumption than in alcohol-naive counterparts.

The frequency of spontaneous glutamatergic transmission and firing of lateral habenula neurons was elevated in withdrawn rats compared to naive rats.
5-HT2 receptor antagonists reduced the increased firing and glutamatergic transmission observed in withdrawn rats.
Acute ethanol administration led to a smaller increase in spontaneous glutamatergic transmission and firing in withdrawn rats than in naive rats.
Intra-lateral habenula infusion of 5-HT2 receptor agonists heightened nociceptive sensitivity in naive rats.
Increased nociceptive sensitivity and alcohol intake in withdrawn rats were associated with reduced activity when treated with 5-HT reuptake blockers or 5-HT2 receptor antagonists.
mRNA for 5-HT2A and 5-HT2C receptors was detected in the lateral habenula.

Simplified

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-HTRs) 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 The basal frequency of sEPSCs and firings was higher in slices of withdrawn rats than that of Naïve rats, and 5-HT2R antagonists attenuated the enhancement.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-HTR antagonists but mimicked by 5-HTR agonists. Importantly, intra-LHb infusion of 5-HTR 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in Naïve rats, while antagonists or 5-HT reuptake blocker decreased nociceptive sensitivity and alcohol intake in withdrawn rats.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-HTR 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-HTR-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. 2 2 2 2 2 2

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Changes in serotonin receptor signaling in the brain's emotion area linked to higher pain sensitivity after alcohol withdrawal in rats

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