Review articleThe hidden side of Parkinson’s disease: Studying pain, anxiety and depression in animal models
Section snippets
The non-motor symptoms in Parkinson’s disease patients
This section provides a rapid overview of some clinical data concerning pain, anxiety and depression in Parkinson’s disease. For more details concerning these clinical aspects, please refer to the following references (Blanchet and Brefel-Courbon, 2017; Chaudhuri et al., 2006; Schapira et al., 2017).
Animal models to study Parkinson’s disease
This section mostly focuses on animal models (rodents and monkeys) of Parkinson’s disease for which data related to pain-, anxiety- or depression-like behaviors are available. For a more exhaustive view of existing models, readers can consult following reviews (Bastías-Candia et al., 2018; Bové and Perier, 2012; Creed and Goldberg, 2018; Francardo, 2018; Grandi et al., 2018; Koprich et al., 2017; Volta and Melrose, 2017).
Nociception and pain in rodent Parkinson’s disease models (Fig. 2)
According to the definition from the International Association for the Study of Pain, pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. This sensory/emotional duality is a critical element. It distinguishes pain from nociception, which encompasses “the neural process of encoding noxious stimuli” and does not necessarily imply the presence of pain. However, distinguishing pain from nociception remains
Conclusion
Beyond dopamine cell loss and motor symptoms, Parkinson’s disease is a complex disease that leads to a variety of non-motor symptoms, including pain, anxiety and depression in a notable proportion of patients. For decades, experimental research on Parkinson’s disease has focused on the motor symptoms as well as on the dopamine system. Indeed, until recently, most data in animal models were limited to dopaminergic alterations, which could not explain Parkinson’s disease semiology, particularly
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the Centre National de la Recherche Scientifique [contracts UPR3212 and UMR5293], the University of Strasbourg, the University of Bordeaux, the Agence Nationale de la Recherche [ANR-15-CE37-0005-02; Euridol ANR-17-EURE-0022], the Fondation pour la Recherche Médicale [FDT20170437322], the NeuroTime Erasmus Mundus Joint Doctorate and by a NARSAD distinguished investigator grant from the Brain and Behavior Research Foundation [24220].
References (243)
- et al.
1-methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain
Eur. J. Pharmacol.
(2003) - et al.
Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice
Nutrition
(2014) Tests and models of nociception and pain in rodents
Neuroscience
(2012)- et al.
The anterior cingulate cortex is a critical hub for pain-induced depression
Biol. Psychiatry
(2015) - et al.
Pain in Parkinson’s disease: prevalence and characteristics
Pain
(2009) Measuring rodent exploratory behavior
- et al.
Pramipexole but not imipramine or fluoxetine reverses the “depressive-like” behaviour in a rat model of preclinical stages of Parkinson’s disease
Behav. Brain Res.
(2014) - et al.
Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease
Prog. Neurobiol.
(2001) - et al.
Neurotoxin-based models of Parkinson’s disease
Neuroscience
(2012) - et al.
Repeated administration of N-methyl-4-phenyl 1,2,5,6-tetrahydropyridine to rats is not toxic to striatal dopamine neurones
Biochem. Pharmacol.
(1984)
Staging of brain pathology related to sporadic Parkinson’s disease
Neurobiol. Aging
Acute ipsilateral hyperalgesia and chronic contralateral hypoalgesia after unilateral 6-hydroxydopamine lesions of the substantia nigra
Exp. Neurol.
Progesterone prevents depression-like behavior in a model of Parkinson’s disease induced by 6-hydroxydopamine in male rats
Pharmacol. Biochem. Behav.
Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons
Exp. Neurol.
Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function
Neurobiol. Dis.
Non-motor symptoms of Parkinson’s disease: diagnosis and management
Lancet Neurol.
Dopaminergic imaging of nonmotor manifestations in a rat model of Parkinson’s disease by fMRI
Neurobiol. Dis.
Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice
J. Biol. Chem.
In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson’s disease?
Exp. Neurol.
Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson’s disease
Neuropharmacology
Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat
Eur. J. Pharmacol.
Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine
Brain Res.
Motivation, reward, and Parkinson’s disease: influence of dopatherapy
Neuropsychologia
Parkinson’s disease: mechanisms and models
Neuron
Chronic Parkinsonism secondary to intravenous injection of meperidine analogues
Psychiatry Res.
Genetic animal models of Parkinson’s disease
Neuron
Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism
Neurobiol. Dis.
Models of depression
Vitam. Horm.
Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson’s disease patients
Parkinsonism Relat. Disord.
Serotonergic neurons mediate the anxiolytic effect of l-DOPA: neuronal correlates in the amygdala
Neurobiol. Dis.
Alpha-synuclein and transgenic mouse models
Neurobiol. Dis.
Modeling Parkinson’s disease and treatment complications in rodents: potentials and pitfalls of the current options
Behav. Brain Res.
Alpha-synuclein transgenic mice exhibit reduced anxiety-like behaviour
Exp. Neurol.
Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein
Neuron
Locomotor differences in mice expressing wild-type human α-synuclein
Neurobiol. Aging
Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1
Neuron
Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse
Behav. Brain Res.
Animal models of early-stage Parkinson’s disease and acute dopamine deficiency to study compensatory neurodegenerative mechanisms
J. Neurosci. Methods
The dependence of the anti-nociceptive effect of morphine and other analgesic agents on spinal motor activity after central monoamine depletion
Eur. J. Pharmacol.
Animal models of Parkinson’s disease: an updated overview
Rev. Neurol. (Paris)
The association between Parkinson’s disease motor impairments and pain
Pain Med.
Diagnostic and Statistical Manual of Mental Disorders
Preclinical models of Parkinson’s disease
Curr. Protoc. Neurosci.
The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease
Mov. Disord.
Midbrain 6-hydroxydopamine lesions modulate blink reflex excitability
Exp. Brain Res.
Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: relevance to sporadic Parkinson’s disease
Environ. Toxicol.
Revisiting the paraquat-induced sporadic parkinson’s disease-like model
Mol. Neurobiol.
Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson’s disease
Folia Neuropathol.
Animal models of Parkinson’s disease
Bioessays
Chronic systemic pesticide exposure reproduces features of Parkinson’s disease
Nat. Neurosci.
Cited by (45)
The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease
2022, IBRO Neuroscience ReportsHuman organotypic brain model as a tool to study chemical-induced dopaminergic neuronal toxicity
2022, Neurobiology of DiseaseCitation Excerpt :The clinical success of the resulting drug candidates was limited with an analysis of 357 clinical trials since 1999 showing the exclusive approval of compounds in a narrow range of symptomatic treatment for PD (Boucherie et al., 2021). This has led to some discussion of the value of these models, for example rodents (Vingill et al., 2018; Faivre et al., 2019). Some authors (Bezard et al., 2013) highlight the superior translational relevance of monkey models but also powerful in vitro alternatives are becoming increasingly available.
Age-related tolerance to paraquat-induced parkinsonism in Drosophila melanogaster
2022, Toxicology LettersAstrocytes and neuropsychiatric symptoms in neurodegenerative diseases: Exploring the missing links
2022, Current Opinion in NeurobiologyCitation Excerpt :Most studies have focused on ‘usual suspects’ involved in major depressive disorder (MDD) that can also be dysregulated in ND. These include the hypothalamus–pituitary–adrenal axis, as well as the neurotransmitter (glutamatergic, GABAergic, dopaminergic) and neuromodulatory (serotoninergic, noradrenergic) systems [8–10]. Interestingly, NDs have both critical differences (distinct pathological mechanisms, primarily vulnerable brain regions) and common features (abnormal neuronal networks, neuroinflammation, misfolded proteins).
Living with the enemy: from protein-misfolding pathologies we know, to those we want to know
2021, Ageing Research ReviewsCitation Excerpt :PD is characterized by heterogeneous clinical features including motor symptoms caused by the loss of dopaminergic neurons in the substantia nigra compacta and the loss of neural circuits in the striatum (Subhramanyam et al., 2019), such as akinesia, muscle rigidity, resting tremor, gait disorders and postural instability. During the development of PD, non-motor symptoms (i.e., neuropsychiatric symptoms, pain, and sleep dysfunction) appear at an early stage due to spreading of α-syn aggregates in the brain (Draoui et al., 2020; Faivre et al., 2019; Tysnes and Storstein, 2017). Neuropathological exams of deep postmortem human brain in Parkinson's disease have revealed the existence of pathological inclusions containing the principally aggregated protein, α-synuclein (α-syn; Fig. 3C).