Understanding the pathophysiology of pain in Parkinson’s disease – PDPAIN

Pain in Parkinson’s disease (PD) is one of the non-motor symptoms contributing to impaired quality of life of patients. Among the different types of pain observed in PD, central pain has the highest severityand appears to be more difficult to treat than the nociceptive pain. A better knowledge of the pathophysiology of this specific pain will enable to guide the choice of an appropriate treatment.
The aim of the present translational proposal is to investigate the pathophysiological mechanisms, involving the monoaminergic systems, at the origin of pain disorders in the mice models of PD, using behavioral, electrophysiological, pharmacological, biochemical, chemo- and optogenetic approaches, and in PD patients using anatomo-pathological and multimodal Neuroimaging approaches. Understanding the role of monoamines in nociceptive integration in the context of PD is crucial in developing successful treatment strategies.
In the present project, we propose to follow specific aims organized in four workpackages:
1. We will characterize pain phenotypes and investigate the consequences of dopaminergic neuron lesion on nociceptive integration and monoamine dynamics in the spinal cord in mice models of PD mimicking the advanced stage of PD (6-OHDA model), and the early and intermediate stages of the disease (alpha synuclein model).
2. We we propose to study the specific chemogenetic and optogenetic modulation of the descending dopaminergic, noradrenergic and serotonergic projection neurons to the spinal cord on mechanical and thermal nociceptive thresholds, on the excitability of dorsal horn neurons of spinal cord and on monoamine dynamics in the spinal cord, in sham and dopamine depleted mice, using transgenic animals.
3. We will investigate the consequences of the perturbation of the descending monoaminergic pathways on the L- and T-type Ca2+ channels-mediated neuronal excitability in the dorsal horn of spinal cord since Ca2+ channels intrinsically control the neuronal excitability at this level.
4. We will investigate the pathophysiology of pain in PD patients. This clinical part of the project proposes to focus on: 1) an anatomo-pathological study of the A11, locus coeruleus and the raphe magnus, three brain nuclei projecting to the spinal cord and involved in the modulation of pain, using immunohistochemistry on brain slices of PD patients and their controls; 2) cerebral neuroimaging and clinical investigations in PD patients with and without central pain in order to investigate the role of the serotonergic system in central pain which is one of the most specific pain in PD. Patients will undergo cerebral imaging positron emission tomography (PET), which allows in vivo imaging of 5HT1A receptors and multimodal brain MRI including morphometric imaging and functional connectivity.
The present translational project is ambitious using innovative methodology and approaches, including transgenic animals, chemogenetic and optogenetic approaches in addition to the recent developed biochemical techniques measuring the dynamic of monoamines. Its originality lies in the use of preclinical and clinical approaches in the same project, which will provide an overview of the problem posed for a better understanding of the pathophysiology of pain in PD patients. As a result, this project could lead to a large clinical trial evaluating drugs targeting the monoaminergic systems in PD patients.