Monoaminergic regulation of nociceptive circuitry in a Parkinson's disease rat model

Campos, Ana Carolina Pinheiro; Berzuino, Miriã Benatti; Hernandes, Marina S.; Fonoff, Erich Talamoni; Pagano, Rosana L.

doi:10.1016/j.expneurol.2019.04.015

Cited by 25 publications

(25 citation statements)

References 89 publications

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“…At the behavioral level, regardless inconsistencies found through the scientific publications, p a r k i n s o n i a n a n i m a l s t e n d t o m i m i c t h e h u m a n symptomatology showing motor but also non-motor impairments (Titova et al, 2017). An array of studies report that rodents lesioned with 6-OHDA or MPTP show anxious and depressive behavior, pain, cognitive, and sleep disturbances (Monaca et al, 2004;Pérez et al, 2009;Berghauzen-Maciejewska et al, 2014;Vo et al, 2014;Kamińska et al, 2017;Charles et al, 2018;Campos et al, 2019;Domenici et al, 2019), more notably in bilateral models of the disease (Ferro et al, 2005;Tadaiesky et al, 2008;Santiago et al, 2010;Bonito-Oliva et al, 2014;Vieira et al, 2019). Although the participation of other nuclei cannot be ruled out, the role of the LC in the mentioned functions is widely accepted.…”

Section: Preclinical Evidencementioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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Section: Preclinical Evidencementioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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“…PD patients and parkinsonian animal models exhibit accelerated and irregular neuronal firing and abnormal oscillations in the local field potential in the basal ganglia nuclei, including the subthalamic nucleus (STN), globus pallidus interna (GPi), and substantia nigra pars reticulata (SNr), and these abnormalities are correlated with motor deficits (11)(12)(13)(14)(15)(16)(17). As the substantia nigra, striatum, and globus pallidus integrate nociceptive information to render pain avoidance and nocifensive behaviors (2,10,18), neural circuit dysfunction in these regions may lead to the hyperalgesia and shortened nociceptive reflex latencies observed in parkinsonian animal models (19)(20)(21)(22)(23). However, addressing the gap between the dysfunction in basal ganglia circuits and pain sensitization in PD requires experiments using sophisticated neuromodulation techniques.…”

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confidence: 99%

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

Luan

Tang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Although pain is a prevalent nonmotor symptom in Parkinson’s disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.

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“…The PD induction model was made as previously described [ 25 , 54 ]. Animals were anesthetized with isoflurane (4% induction, 2.5% maintenance in 100% oxygen) associated with local anesthesia (2% lidocaine, 100 μL/animal on the scalp).…”

Section: Methodsmentioning

confidence: 99%

“…However, long-term dopaminergic therapy can lead to undesirable effects, such as motor fluctuations during off-periods of the drug, dyskinesia, and pain hypersensitivity, which are associated with disease progression and drug exposure; this, in turn, exponentially worsens quality of life [ 18 , 19 , 20 ]. Beside dopamine, serotonin deficit also plays a major role in PD pathophysiology and is related to nonmotor symptoms such as pain and depression [ 21 , 22 , 23 , 24 , 25 ]. In rodent PD model, a deficiency in the descending analgesic pathways results in opioidergic deficit, glial activation, and neuronal hyperexcitability in the dorsal horn of the spinal cord (DSHC), leading to increased central sensitization and consequent pain syndrome [ 17 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Beside dopamine, serotonin deficit also plays a major role in PD pathophysiology and is related to nonmotor symptoms such as pain and depression [ 21 , 22 , 23 , 24 , 25 ]. In rodent PD model, a deficiency in the descending analgesic pathways results in opioidergic deficit, glial activation, and neuronal hyperexcitability in the dorsal horn of the spinal cord (DSHC), leading to increased central sensitization and consequent pain syndrome [ 17 , 25 , 26 ]. Hence, we hypothesized that therapeutic approaches based on the reinforcement of descending analgesic control may be more effective for pain management in PD patients.…”

Section: Introductionmentioning

confidence: 99%

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Motor Cortex Stimulation Reversed Hypernociception, Increased Serotonin in Raphe Neurons, and Caused Inhibition of Spinal Astrocytes in a Parkinson’s Disease Rat Model

Campos

Berzuino

Barbosa

et al. 2021

Cells

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Persistent pain is a prevalent symptom of Parkinson’s disease (PD), which is related to the loss of monoamines and neuroinflammation. Motor cortex stimulation (MCS) inhibits persistent pain by activating the descending analgesic pathways; however, its effectiveness in the control of PD-induced pain remains unclear. Here, we evaluated the analgesic efficacy of MCS together with serotonergic and spinal glial modulation in an experimental PD (ePD) rat model. Wistar rats with unilateral striatal 6-OHDA and MCS were assessed for behavioral immobility and nociceptive responses. The immunoreactivity of dopamine in the substantia nigra and serotonin in the nucleus raphe magnus (NRM) and the neuronal, astrocytic, and microglial activation in the dorsal horn of the spinal cord were evaluated. MCS, without interfering with dopamine loss, reversed ePD-induced immobility and hypernociception. This response was accompanied by an exacerbated increase in serotonin in the NRM and a decrease in neuronal and astrocytic hyperactivation in the spinal cord, without inhibiting ePD-induced microglial hypertrophy and hyperplasia. Taken together, MCS induces analgesia in the ePD model, while restores the descending serotonergic pathway with consequent inhibition of spinal neurons and astrocytes, showing the role of MCS in PD-induced pain control.

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Monoaminergic regulation of nociceptive circuitry in a Parkinson's disease rat model

Cited by 25 publications

References 89 publications

The Noradrenergic System in Parkinson’s Disease

The Noradrenergic System in Parkinson’s Disease

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

Motor Cortex Stimulation Reversed Hypernociception, Increased Serotonin in Raphe Neurons, and Caused Inhibition of Spinal Astrocytes in a Parkinson’s Disease Rat Model

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