Investigation of neuroinflammation in pain in Parkinson’s disease

Student thesis: Doctoral ThesisDoctor of Philosophy


Parkinson’s Disease (PD) is a multisystem disorder with both motor and non-motor symptoms (NMS). Pain is one of the most common and incapacitating NMS, with a prevalence that ranges from 40% to 85%, occurring early in the progression of the disease. However, the aetiology of pain in PD is poorly understood and inadequately treated in people with PD (PwP). Neuroinflammation is a well-established feature of PD and has been implicated in the neurodegenerative side of the disorder. In other chronic pain conditions, neuroinflammation has been implicated in pain development and maintenance. Several studies in PD have shown reduced intraepidermal nerve fiber density (IENFD), but whether this is accompanied by inflammatory changes and whether these contribute to pain in PD remains elusive. We set out to test the overall hypothesis that neuroinflammation in pain-related regions in the central and peripheral nervous system is involved in pain in PD. To address this hypothesis, we performed preclinical and clinical experiments. For the preclinical part, we utilized two rodent models of PD resembling early stages of the disorder, namely the 6-hydroxydopamine (6-OHDA) partial lesioned and the rotenone rat models. We performed intracerebral and intraperitoneal (i.p.) toxin/drug administration, in vivo behavioural assessments, and immunohistochemical analysis of the brain, spinal cord, and skin. For the clinical experiments, we performed pain characterization of PwP using pain scales and then performed quantitative real time polymerase chain reaction (qRT-PCR) for inflammatory markers in skin biopsies. Our preclinical results show the presence of neuroinflammation in pain-related regions of the brain [central thalamus, zona incerta (ZI)] and the dorsal horn of the spinal cord in parkinsonian rats accompanied by reduced opioidergic tone and nociceptive mechanical thresholds. In further support of our hypothesis, administration of an anti-inflammatory compound, the glucagon like peptide-1 receptor (GLP1R) agonist, exenatide reversed the mechanical allodynia in parkinsonian rats by supressing neuroinflammation in the central thalamus and ZI. Our clinical results showed higher expression of interleukin-2 (IL-2) and tumour necrosis factor-α (TNF-α) in PD skin compared to healthy controls but there was no difference between PwP with and without pain. Neither was there any correlation between the IENFD loss and pain intensity in PwP. In conclusion, we provide evidence of central inflammatory changes in pain-related regions in parkinsonian rats, which may contribute to mechanical allodynia seen in these animals, as well as a reverse of this phenotype using an anti-inflammatory drug. Moreover, our clinical data indicate an inflammatory response in the skin of PwP, however, they do not suggest this occurring as a supporting factor to the expression of pain in PD.
Date of Award1 Jun 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSusan Duty (Supervisor), Kallol Ray Chaudhuri (Supervisor) & Nurcan Üçeyler (Supervisor)

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