Abstract
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.
Highlights
Parkinson’s disease (PD) is a progressive and complex neurodegenerative disease that presents with bradykinesia, akinesia, and gait balance, mainly due to severe loss of dopaminergic neurons within the nigrostriatal pathway [1,2,3]
The ramification index (RI) of 6-OHDA animals, regardless of whether they were subjected to Motor cortex stimulation (MCS), was approximately 1 (±0.3), while that of saline animals, regardless of whether they were stimulated, was approximately 2.5 (±1.7) (Figure 4C). These findings showed that animals subjected to the PD model presented hypertrophic microglia in the dorsal horn of the spinal cord (DHSC) when compared with the control group and that MCS did not interfere with microglial activation in the spinal cord (Figure 4C)
We previously demonstrated that the bilateral hypernociception induced by unilateral striatal 6-OHDA model is accompanied by expressive bilateral loss of the descending analgesic pathway and spinal opioid system together with glial activation in the DHSC [25]
Summary
Parkinson’s disease (PD) is a progressive and complex neurodegenerative disease that presents with bradykinesia, akinesia, and gait balance, mainly due to severe loss of dopaminergic neurons within the nigrostriatal pathway [1,2,3]. Dopamine replacement in PD patients and experimental models has shown positive results in decreasing pain sensitivity [15,16,17]. 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]. 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]. We hypothesized that therapeutic approaches based on the reinforcement of descending analgesic control may be more effective for pain management in PD patients
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