PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson’s disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons  

作　　者：Li-guo Dong Meng-qi An Han-ying Gu Li-ge Zhang Jin-bao Zhang Cheng-jie Li Cheng-jie Mao Fen Wang Chun-feng Liu 

机构地区：[1]Department of Neurology and Clinical Research Center of Neurological Disease,The Second Affiliated Hospital of Soochow University,Suzhou,215004,China [2]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience,Soochow University,Suzhou,215123,China [3]Department of Neurology,The Affiliated Hospital of Xuzhou Medical University,Xuzhou,221000,China [4]Department of Neurology,The Second Affiliated Hospital of Xinjiang Medical University,Urumqi,830063,China

出　　处：《Acta Pharmacologica Sinica》2023年第12期2418-2431,共14页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(82071420,82271279);Jiangsu Provincial Key R&D Program(BE2018658);the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。

摘　　要：Pain is a common annoying non-motor symptom in Parkinson’s disease(PD)that causes distress to patients.Treatment for PD pain remains a big challenge,as its underlying mechanisms are elusive.Pituitary adenylate cyclase-activating polypeptide(PACAP)and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes.In this study,we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain.6-hydroxydopamine(6-OHDA)-induced PD model was established in rats.Behavioral tests,electrophysiological and Western blotting analysis were conducted 3 weeks later.We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50%threshold in von Frey filament test and shorter tail flick latency,while mRNA levels of Pacap and Adcyap1r1(gene encoding PAC1-R)in the spinal dorsal horn were significantly upregulated.Whole-cell recordings from coronal spinal cord slices at L4–L6 revealed that the frequency of spontaneous excitatory postsynaptic currents(sEPSCs)in dorsal horn neurons was significantly increased,which was reversed by application of a PAC1-R antagonist PACAP 6–38(250 nM).Furthermore,we demonstrated that intrathecal microinjection of PACAP 6–38(0.125,0.5,2μg)dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats.Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase(ERK)in spinal dorsal horn of 6-OHDA rats.Microinjection of pAAV-Adcyap1r1 into L4–L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats.Intrathecal microinjection of ERK antagonist PD98059(10μg)significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons.In addition,we found that serum PACAP-38 concentration was significantly increased in PD patients with pain,and positively correlated with numerical rating scale score.In conclusion,activation of PACAP/PAC1-R induces the develo

关 键 词：Parkinson’s disease HYPERALGESIA pituitary adenylate cyclase-activating polypeptide PAC1-R spinal cord dorsal horn sEPSCs 

分 类 号：R285.5[医药卫生—中药学]