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Background Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multipotent neuropeptide widely distributed in the trigeminovascular system (TVS) and higher brain regions. At present, the underlying mechanism of PACAP/PACAP type1 (PAC1) receptor in migraine generation remains unclear. Methods The rat model of chronic migraine (CM) was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and hot plate tests were used to measure the mechanical and thermal thresholds. The expression levels of c-Fos, calcitonin gene-related peptide (CGRP), PACAP, PAC1, protein kinase A (PKA) and phosphorylated extracellular signal-regulated kinase (ERK) were assessed by western blotting or immunofluorescence staining. The internalization of PAC1 receptor was visualized by fluorescence microscope and laser scanning confocal microscope. Results The results showed that c-Fos and CGRP expression significantly increased after repeated administrations of NTG or PACAP. Pitstop2 notably improved hyperalgesia in CM rats, while PACAP6–38 offered no benefit. In addition, PACAP-induced PAC1 receptor internalization, PKA and ERK pathways activation were blocked by Pitstop2 instead of PACAP6–38. Conclusions Our results demonstrate that inhibition of PAC1 receptor internalization could effectively improve allodynia in CM rats by restraining ERK signaling pathway activation in a chronic migraine rat model. Modulation of receptor internalization may be a novel perspective to explore specific mechanisms of PACAP signaling activation in the trigeminal vascular system. 

Abstract Low clouds frequent the subtropical northeastern Pacific Ocean (NEP) and interact with the local sea surface temperature (SST) to form positive feedback. Wind fluctuations drive SST variability through wind–evaporation–SST (WES) feedback, and surface evaporation also acts to damp SST. This study investigates the relative contributions of these feedbacks to NEP SST variability. Over the summer NEP, the low cloud–SST feedback is so large that it exceeds the evaporative damping and amplifies summertime SST variations. The WES feedback causes the locally enhanced SST variability to propagate southwestward from the NEP low cloud deck, modulating El Niño–Southern Oscillation (ENSO) occurrence upon reaching the equator. As a result, a second-year El Niño tends to occur when there are significant warm SST anomalies over the subtropical NEP in summer following an antecedent El Niño event and a second-year La Niña tends to occur when there are significant cold SST anomalies over the subtropical NEP in summer following an antecedent La Niña event The mediating role of the NEP low cloud–SST feedback is confirmed in a cloud-locking experiment with the Community Earth System Model, version 1 (CESM1). When the cloud–ocean coupling is disabled, SST variability over the NEP weakens and the modulating effect on ENSO vanishes. The nonlocal effect of the NEP low cloud–SST feedback on ENSO has important implications for climate prediction.