Abstract
BackgroundCentral sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity.MethodsA CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining.ResultsOur results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899.ConclusionsOur findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.
Highlights
Chronic migraine (CM), with the criteria of ≥ 15 headache days per month and the migraine headache at least 8 days per month, has a high disability rate and large disease burden [1]
Our findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via oxytocin receptor (OTR) in chronic migraine (CM)
The effect of OT has closely associated with the down-regulation of adenylyl cyclase 1 (AC1)/protein kinase A (PKA)/ phosphorylation of CREB (pCREB) signaling pathway, which is activated in CM model
Summary
Chronic migraine (CM), with the criteria of ≥ 15 headache days per month and the migraine headache at least 8 days per month, has a high disability rate and large disease burden [1]. OT exerts its effect via oxytocin receptors (OTRs), which is G-protein-coupled receptors [11]. Another research demonstrates a slightly elevated OT level in blood samples in interictal CM patients [14]. These results imply that OT and OTR may regulate headache through their actions in the central and peripheral regions of the trigeminovascular system. Central sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. The antinociceptive effect of OT and the underlying mechanism in CM remains unclear. We explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity
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