Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789186
Title: Autoantibodies produce pain in Complex Regional Pain Syndrome by sensitizing nociceptors
Author: Cuhadar, Ulku
ISNI:       0000 0004 8500 0746
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
Complex Regional Pain Syndrome (CRPS) is a severe chronic pain condition that typically develops after a trauma such as bone fracture or surgery. CRPS pain is typically confined to the injured limb and exceeds the intensity and duration that can be expected from the initiating trauma. The neurophysiological basis of pain in CRPS is unknown and there are no effective therapies or diagnostic tests available. Plasma exchange has been shown to alleviate pain in long-standing CRPS patients in a small trial, indicating involvement of humoral factors. The aim of my project was to determine the neurophysiological mechanisms responsible for pain and hypersensitivity experienced by CRPS patients using a translational mouse model. In this model, a paw incision is used as a minor experimental trauma in combination with passive transfer of IgG purified from CRPS patients or healthy control subjects. Administration of IgG from CRPS patients, but not from healthy control subjects, exacerbated and prolonged the mechanical and thermal hypersensitivities produced by a paw incision, but did not alter tactile sensitivity to stimulation with von Frey filaments. Passive transfer of CRPS thus recapitulated the sensory profile observed in quantitative sensory testing studies of patients. Electrophysiological studies of skin-nerve preparations identified an increased ectopic impulse frequency in CRPS-IgG treated mice, indicative of spontaneous pain or paraesthesias. Single-unit recordings in the same preparations revealed an increased evoked impulse rate in mechano-nociceptors, whereas low threshold mechanosensitive afferents appeared functionally intact. Single-unit recordings were made in saphenous afferents innervating the hairy, dorsal paw skin, to reduce the impact of post-surgical sensitization. The observed sensitization of nociceptors innervating the hairy skin is consistent with the limb-confined pain typical of CRPS. Overnight incubation of isolated DRG neurons with CRPS-IgG, enhanced the Ca2+-response produced by a low concentration of K+ in a subpopulation of neurons, suggesting that autoantibodies directly increased neuronal excitability. Immunohistochemical analysis revealed the presence of human IgG in glabrous skin of CRPS and HC-IgG injected mice, with a more pronounced staining or deposit around the incision. Together, these observations suggest that CRPS autoantibodies may act by binding to novel epitopes presented in the post-traumatic environment and that binding may stimulate release of mediators that diffuse locally. Alternatively, the trauma may trigger CRPS by facilitating extravascularization of autoantibodies, exposing peripheral tissues and nerves to higher local titers. In conclusion, my results demonstrate that passively transferred CRPS pain is caused by sensitization of nociceptors.
Supervisor: Andersson, David Armand ; Bevan, Stuart John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789186  DOI: Not available
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