PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

Abstract

Aims Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. Methods Sprague–Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. Results The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. Conclusions Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.

Role of Neurotrophins in Orofacial Pain Modulation: A Review of the Latest Discoveries

“…The study showed that PACAP and PACAP type 1 receptor (PAC1R) expression were significantly raised in the Sp5C after repeated nitroglycerin injections. Therefore, the synthesis of BDNF rose when synaptic activity increased, indeed BDNF expression levels significantly increased after nitroglycerin injection, and the PAC1R antagonist, PACAP6-38, reversed the effects [106]. These results indicated that PACAP6-38 was capable of improving synaptic transmission and neuronal activation involving BDNF, the extracellular signal-regulated kinase, and the cAMP response element-binding protein (BDNF-ERK-CREB) pathway in chronic migraine rats [106].…”

“…Therefore, the synthesis of BDNF rose when synaptic activity increased, indeed BDNF expression levels significantly increased after nitroglycerin injection, and the PAC1R antagonist, PACAP6-38, reversed the effects [106]. These results indicated that PACAP6-38 was capable of improving synaptic transmission and neuronal activation involving BDNF, the extracellular signal-regulated kinase, and the cAMP response element-binding protein (BDNF-ERK-CREB) pathway in chronic migraine rats [106]. The BDNF-ERK-CREB pathway is fundamental for neuronal survival, synapses, and synaptic plasticity and it is also involved in cognitive impairment [107,108].…”

“…In this section, 6 original research articles and 0 clinical trials were included and analyzed. Very recently, an in vivo study using a rat model of chronic migraine established by repeated injections of nitroglycerin [106] suggested that pituitary adenylate cyclaseactivating peptide (PACAP) induces migraine-like attacks and may potentially be a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. The study showed that PACAP and PACAP type 1 receptor (PAC1R) expression were significantly raised in the Sp5C after repeated nitroglycerin injections.…”

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment

“…In animal models, PACAP has been shown to play a role in trigeminal sensitization, which is the process by which nociceptive signals become amplified and persistent, leading to chronic pain [137]. Studies have also found that PACAP is involved in the activation of inflammatory pathways in the trigeminal nerve, further contributing to pain and inflammation [138].…”

From CGRP to PACAP: Unraveling the Next Chapter in Migraine Treatment

“…In animal models, PACAP has been shown to play a role in trigeminal sensitization, which is the process by which nociceptive signals become amplified and persistent, leading to chronic pain [131]. Studies have also found that PACAP is involved in the activation of inflammatory pathways in the trigeminal nerve, further contributing to pain and inflammation [132].…”