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Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson’s Disease

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Abstract

Pain in Parkinson’s disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 μmol/L) and palosetron (10 μmol/L), but not 5-HT3 receptor agonist m-CPBG (30 μmol/L) and SR 57,727 (10 μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 μmol/L) and eptapirone (10 μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 μmol/L) and p-MPPI (10 μmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

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Data Availability

The datasets generated in the current research are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

5-HT:

5-Hydroxytryptamine; serotonin

AP:

Action potential

PD:

Parkinson’s disease

SDH:

Spinal dorsal horn

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

L4-L6:

Fourth to sixth lumbar spinal cord

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Funding

This work was supported by the National Natural Science Foundation of China (81801258), Natural Science Foundation of Jiangsu Province (BK20170355), Jiangsu Provincial social development projects (BE2018658, BE201765), Gusu Health Talents Training Project (GSWS2019041, GSWS2020035), Discipline Construction Program of the Second Affiliated Hospital Soochow University (XKTJ-XK202001 and XKTJ-XK202004), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. Cheng-Jie Li and Li–Ge Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China

    Cheng-Jie Li, Li-Ge Zhang, Li-guo Dong, Han-Ying Gu, Yong-Ping Dai, Fen Wang, Cheng-Jie Mao & Chun-Feng Liu

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

    Cheng-Jie Li, Li-Ge Zhang, Lu-Bing Liu, Meng-Qi An, Li-guo Dong, Fen Wang & Chun-Feng Liu

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

    Chun-Feng Liu

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Contributions

FW, CJM, and CFL designed the study. CJL, LGZ, LBL, and MQA performed the experiments and collected data. CJL, LGZ, LBL, MQA, LGD, HYG, and YPD performed data analysis and interpretation. CJL and LGZ drafted the article, FW and CJM revised it critically for important intellectual content, and FW gave final approval of the version to be submitted.

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Correspondence to Fen Wang or Cheng-Jie Mao.

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This study was approved by the Animal Use and Care Committee of Soochow University and followed the guidelines of the International Association for the Study of Pain.

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Li, CJ., Zhang, LG., Liu, LB. et al. Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson’s Disease. Mol Neurobiol 59, 7253–7264 (2022). https://doi.org/10.1007/s12035-022-03034-8

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