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Exercise Improves Orofacial Pain and Modifies Neuropeptide Expression in a Rat Model of Parkinson’s Disease

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Abstract

Pain is a common non-motor symptom of Parkinson's disease (PD), which often occurs in the early disease stages. Despite the high prevalence, it remains inadequately treated. In a hemi-parkinsonian rat model, we aimed to investigate the neurochemical factors involved in orofacial pain development, with a specific focus on pain-related peptides and cannabinoid receptors. We also evaluated whether treadmill exercise could improve orofacial pain and modulate these mechanisms. Rats were unilaterally injected in the striatum with either 6-hydroxydopamine (6-OHDA) or saline. Fifteen days after stereotactic surgery, the animals were submitted to treadmill exercise (EX), or remained sedentary (SED). Pain assessment was performed before the surgical procedure and prior to each training session. Pain-related peptides, substance P (SP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid type 1 (TRPV1) activation and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated in the trigeminal nucleus. In order to confirm the possible involvement of cannabinoid receptors, we also injected antagonists of CB1 and CB2 receptors. We confirmed the presence of orofacial pain after unilateral 6-OHDA-injection, which improved after aerobic exercise training. We also observed increased pain-related expression of SP, CGRP and TRPV1 and decreased CB1 and CB2 in the trigeminal ganglion and caudal spinal trigeminal nucleus in animals with PD, which was reversed after aerobic exercise training. In addition, we confirm the involvement of cannabinoid receptors since both antagonists decreased the nociceptive threshold of PD animals. These data suggest that aerobic exercise effectively improved the orofacial pain associated with the PD model, and may be mediated by pain-related neuropeptides and cannabinoid receptors in the trigeminal system.

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Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (2015/24256-0; 2014/24533-0; 2017/26821-1; 2017/05218-5, 2021/02897-4) and Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (157284/2017-4; 405853/2018-1) supported this study (Brazil). The funding agencies play no role in the design of the study, data collection, analysis, interpretation of the data, or in writing the manuscript.

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  1. Marucia Chacur and Daniel Oliveira Martins contributed equally to this manuscript.

Authors and Affiliations

  1. Laboratory of Neuroscience, Hospital Sírio-Libanês, Rua Daher Cutait, 69, 05508-000, São Paulo, SP, Brazil

    Daniel Oliveira Martins

  2. Department of Anatomy, Laboratory of Functional Neuroanatomy of Pain, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil

    Karina Henrique Binda, Marucia Chacur & Daniel Oliveira Martins

  3. Department of Nuclear Medicine and PET Centre, Aarhus University, Aarhus, Denmark

    Karina Henrique Binda

  4. Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

    Karina Henrique Binda

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  1. Karina Henrique Binda
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Contributions

All authors made substantial contributions to the following tasks of research: initial conception (Martins D.O.; Binda, K.H.); design (Martins D.O.; Binda, K.H., Chacur M.); provision of resources (Chacur M.); collection of data (Martins D.O.; Binda, K.H.); analysis and interpretation of data (Martins D.O.; Binda, K.H.); writing the first draft of the paper or important intellectual content (Martins D.O.; Binda, K.H.); revision of paper (Martins D.O.; Binda, K.H.; Chacur M.).

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Correspondence to Daniel Oliveira Martins.

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The Institutional Animal Care Committee approved the study of the Institute of Biomedical Sciences, University of São Paulo (protocol number 4860310118). This study is reported following the ARRIVE guidelines (http://www.nc3rs.org.uk/arrive-guidelines).

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Binda, K.H., Chacur, M. & Martins, D.O. Exercise Improves Orofacial Pain and Modifies Neuropeptide Expression in a Rat Model of Parkinson’s Disease. Neurotox Res 41, 459–470 (2023). https://doi.org/10.1007/s12640-023-00651-6

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