Abstract
Pain is a key non-motor feature of Parkinson's disease (PD) that significantly impacts on the quality of life of people with this condition. The mechanisms underlying chronic pain in PD are poorly understood hence the lack of effective treatments. Thus, an in depth understanding of the cellular and molecular mechanisms involved in the initiation and sustainment of pain may provide novel targets for pharmacological intervention. Pain has been shown to develop during the premotor stages of the disease in which PD pathology, via post-mortem investigations, has been reported to be present in areas known to control both ascending and descending pain pathways. Such regions include areas of the brainstem and lower midbrain, in particular, the periaqueductal grey (PAG), locus coeruleus, and Raphé nuclei. Despite this, little is known about whether these pathological changes in PD have any effect on pain perception.To understand this condition, the well established 6-OHDA nigrostriatal lesioned rat model was used to identify pathological changes in the above mentioned pain-related regions of the CNS. This allowed us to identify key pathological changes in the PAG and spinal cord, namely dopaminergic cell loss in the PAG and concomitant met-enkephalin reductions in the dorsal horn of the spinal cord. We further found that the dopaminergic cells of the PAG drive antinociception by activating local glutmatergic neurons via dopamine receptor D5. We further show in the parkinsonian state, that the loss of dopaminergic tone in the PAG causes a reduction in Raphé magnus activity in the brainstem via this lost PAG-glutamatergic stimulation. We lastly were able to identify the same pathological changes in post-mortem human PD PAG and spinal cord samples. Furthermore, we were able to identify increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life.
Our discoveries have outlined pathological pathways involved in the manifestation of pain in PD and offer mechanistic insight into a symptom that has largely been inadequately treated. Our findings, therefore, highlight numerous therapeutic targets, e.g. D5 receptor agonists, serotonergic reuptake inhibitors, and anti-inflammatories, that may offer symptomatic relief for people with PD worldwide.
| Date of Award | 1 Oct 2022 |
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| Original language | English |
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| Supervisor | Susan Duty (Supervisor) & Marzia Malcangio (Supervisor) |