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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

Acta Pharmacologica Sinica volume 44, pages 2418–2431 (2023)Cite this article

Abstract

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, 2 μg) 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 (10 μg) 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 development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

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Fig. 1: Behavior tests and level of PACAP-38 in spinal dorsal horn of rats after bilateral lesions of SNpc DA neurons with 6-OHDA.
Fig. 2: Inhibiting PACAP/PAC1-R by PACAP 6–38 attenuated hyperalgesia in 6-OHDA-lesioned rats.
Fig. 3: Inhibiting PACAP/PAC1-R signaling relieved the enhanced sEPSCs of the spinal dorsal horn neurons of 6-OHDA rats.
Fig. 4: PACAP/PAC1-R upregulated the phosphorylation of CaMKII and ERK, but not P38, in the spinal dorsal horn of 6-OHDA rats.
Fig. 5: Microinjection of pAAV-Adcyap1r1 into the L4–L6 spinal dorsal horn alleviated 6-OHDA-lesion-induced mechanical allodynia and thermal hyperalgesia in rats.
Fig. 6: Inhibition of ERK alleviated hyperalgesia and decreased excitatory synaptic transmission of spinal dorsal horn neurons of 6-OHDA-lesioned rats.
Fig. 7: Correlation analysis of serum PACAP-38 levels and pain severity.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82071420, 82271279), Jiangsu Provincial Key R&D Program (BE2018658), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Guang-yin Xu for critical discussions of the data in the manuscript.

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Authors and Affiliations

  1. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Li-guo Dong, Han-ying Gu, Li-ge Zhang, Jin-bao Zhang, Cheng-jie Li, Cheng-jie Mao, Fen Wang & Chun-feng Liu

  2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, 215123, China

    Li-guo Dong, Meng-qi An, Jin-bao Zhang, Fen Wang & Chun-feng Liu

  3. Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China

    Li-guo Dong

  4. Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China

    Chun-feng Liu

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CFL designed the study, and revised the manuscript. FW performed experiments, supervised the experiments and edited the manuscript. CJM collected data and edited the manuscript. LGD performed experiments, collected data, analyzed data and prepared figures and the manuscript. MQA performed experiments, collected data, and prepared figures. HYG, LGZ, CJL, and JBZ performed experiments and analyzed data. All the authors have read and approved the paper. The authors have no conflicts of interest to declare.

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Dong, Lg., An, Mq., Gu, Hy. et al. 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. Acta Pharmacol Sin 44, 2418–2431 (2023). https://doi.org/10.1038/s41401-023-01141-3

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