| Field |
Value |
| NCT Number |
NCT06008704 |
| Status |
Recruiting |
| Sponsor |
University research (France/Switzerland) |
| Phase |
Observational |
| Intervention |
[18F]-MPPF PET scan + MRI |
Pain is a common non-motor symptom in Parkinson's disease, affecting up to 60% of patients. While dopaminergic mechanisms have been extensively studied, the serotonin system may play a key role in PD-related central pain.
¶ Prevalence and Impact
Pain in PD is a significant contributor to disability and reduced quality of life:
- 60% of PD patients experience pain during disease progression
- Pain often precedes motor symptoms by years
- Pain is underreported and undertreated in PD
- Pain scores correlate with depression and anxiety
The King's College Hospital classification divides PD pain into five categories:
- Musculoskeletal pain: Rigidity, cramps, arthralgia
- Neuropathic pain: Burning, stabbing, tingling
- Akathitic pain: Restlessness, inability to remain still
- Primary axial pain: Neck, trunk, lower back pain
- Central pain: Diffuse, burning, often unresponsive to dopaminergic therapy
Central pain is the focus of this trial and is characterized by:
- Spontaneous burning or aching sensation
- Often bilateral and symmetric
- Not relieved by dopaminergic medications
- Associated with sensory abnormalities
The serotonin system is implicated in pain processing through multiple mechanisms:
The 5-HT1A receptor is a G-protein coupled receptor (GPCR) that:
- Couples to Gi/o proteins, inhibiting adenylate cyclase
- Is abundantly expressed in:
- Dorsal raphe nucleus (primary serotonergic nucleus)
- Hippocampus (CA1, CA3 regions)
- Amygdala
- Cortex (layer V pyramidal neurons)
- Spinal cord dorsal horn
-
Descending inhibitory pathways:
- 5-HT1A receptors in the rostral ventromedial medulla (RVM)
- Activation inhibits nociceptive transmission in dorsal horn
- Dysregulation leads to pain amplification
-
Supraspinal modulation:
- 5-HT1A in thalamus and cortex modulates pain perception
- Altered receptor binding correlates with pain severity
-
Integration with dopaminergic circuits:
- Serotonin-dopamine interactions in basal ganglia
- 5-HT1A receptors modulate striatal dopamine release
- Combined dysfunction may explain treatment-resistant pain
Multiple factors contribute to serotonin system impairment in PD:
-
Lewy body pathology:
- Serotonergic neurons in dorsal raphe are susceptible
- Loss of 5-HT neurons correlates with disease stage
-
Neurotransmitter interactions:
- Dopamine loss disrupts serotonergic feedback loops
- Reduced 5-HT1A autoreceptor function
-
Medication effects:
- Dopaminergic medications may affect serotonin transmission
- SSRIs and other serotonergic drugs commonly used
-
Neuroinflammation:
- Activated microglia in pain processing regions
- Cytokines alter serotonin receptor function
- Type: Observational (biomarker study)
- Imaging:
- [18F]-MPPF PET: Visualizes 5-HT1A serotonin receptors
- Multimodal MRI: Morphometric and functional connectivity analysis
- Population:
- PD patients with central pain
- PD patients without central pain (controls)
[18F]-MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-fluorobenzamido]ethyl-piperazine) is a PET radiotracer with ideal properties for 5-HT1A imaging:
| Property |
Value |
| Half-life |
109.8 minutes |
| Specific activity |
>37 GBq/μmol |
| Kd for 5-HT1A |
0.6-1.3 nM |
| Selectivity |
>100x over other 5-HT receptors |
-
Baseline MRI:
- T1-weighted MPRAGE for anatomical reference
- T2-weighted FLAIR for pathology assessment
- Diffusion tensor imaging (DTI) for white matter integrity
-
PET acquisition:
- 60-minute dynamic acquisition after injection
- Reconstruction with attenuation correction
- Regional binding potential (BPND) calculation
-
Analysis approaches:
- Region-of-interest (ROI) analysis
- Voxel-based analysis (SPM)
- Parametric imaging
Structural MRI:
- Voxel-based morphometry (VGM) for gray matter volume
- Cortical thickness analysis
Functional MRI:
- Resting-state functional connectivity
- Pain-processing task activation
Diffusion MRI:
- Fractional anisotropy (FA) mapping
- Tractography of pain pathways
- Peripheral receptors: Nociceptors detect tissue damage
- Spinothalamic tract: Primary pain pathway to thalamus
- Thalamic nuclei: Ventral posterolateral (VPL) nucleus
- Somatosensory cortex: Primary pain perception
- Insula and ACC: Emotional and cognitive pain components
The basal ganglia play a crucial role in pain processing:
- Striatum: Receives pain-related input, modulates perception
- Substantia nigra: Dopaminergic pain inhibition
- Globus pallidus: Output to thalamus
5-HT1A receptors modulate pain at multiple levels:
| Level |
Mechanism |
Effect |
| Spinal cord |
Presynaptic inhibition of primary afferents |
Reduced nociceptive input |
| Brainstem |
RVM modulation of descending pathways |
Enhanced inhibition |
| Thalamus |
Thalamic relay modulation |
Altered sensory gating |
| Cortex |
Cortical processing integration |
Pain perception modulation |
This biomarker study addresses critical questions:
-
Is there altered 5-HT1A receptor binding in PD patients with central pain?
- Expected: Reduced binding in raphe, thalamus, insula
-
Are there specific brain regions where serotonin dysfunction correlates with pain severity?
- Expected: Correlation with pain questionnaire scores
-
How does serotonin dysfunction relate to other PD pathologies?
- Expected: Association with disease duration, motor severity
This biomarker study may:
-
Identify new therapeutic targets: Serotonergic drugs for PD pain
- 5-HT1A agonists (e.g., tandospirone, buspirone)
- SSRI/SNRI augmentation strategies
-
Improve pain diagnosis: Biomarkers for central vs peripheral pain
- Differentiate pain subtypes
- Guide treatment selection
-
Elucidate pain mechanisms: Understanding non-dopaminergic contributions
- Explain treatment resistance
- Identify novel pathways
Understanding serotonin dysfunction could lead to:
-
Personalized medicine:
- PET imaging to select patients for serotonergic therapy
- Response prediction based on receptor status
-
Drug development:
- Targeted 5-HT1A agonists for PD pain
- Combination approaches
-
Repurposing opportunities:
- Existing serotonergic drugs for new indications
- Fast-track clinical translation
- Pain in Parkinson's Disease: Exploration of the Serotonin System in PET - NCT06008704
- 18F-MPPF PET for Serotonin 5-HT1A Receptor Imaging
- Serotonin and Pain in Parkinson's Disease - NeuroWiki
- Pain in Parkinson's Disease: Prevalence and Risk Factors (2023)
- Central Pain in Parkinson's Disease: Mechanisms and Treatment (2022)
- 5-HT1A Receptor Imaging in Neuropsychiatric Disorders (2021)