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.

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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 44 Issue 12 Pg. 2418-2431 (Dec 2023) ISSN: 1745-7254 [Electronic] United States
• PMID: 37563446 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Chemical References

• Pituitary Adenylate Cyclase-Activating Polypeptide
• Oxidopamine
• Extracellular Signal-Regulated MAP Kinases
• Adcyap1r1 protein, rat
• Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I

Topics

• Rats
• Humans
• Animals
• Pituitary Adenylate Cyclase-Activating Polypeptide (pharmacology, metabolism)
• Hyperalgesia (drug therapy, metabolism)
• Oxidopamine
• Parkinson Disease (drug therapy)
• Synaptic Transmission
• Pain
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Posterior Horn Cells (metabolism)
• Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I (metabolism)