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Functional reorganisation of dorsal horn neurones in chronic neuropathic pain : new opportunities for new therapies
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Campbell-Galland, Adam T. (2022) Functional reorganisation of dorsal horn neurones in chronic neuropathic pain : new opportunities for new therapies. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3877409
Abstract
Chronic neuropathic pain is a condition suffered by millions globally. Despite increases in our knowledge of the molecular-genetic and anatomical plasticity associated with neural pathways in chronic pain states, still little is known of the functional adaptations that occur in neuropathic pain at the spinal level. The principal objective was to use electrophysiology to characterise intrinsic membrane and extrinsic synaptic properties of lamina I/II dorsal horn neurones in a neuropathic pain state. These neurones are critical for integration and processing of sensory input from the periphery, including nociceptive input, and formulation of output to higher centres in the brain. To achieve the objective whole-cell patch-clamp electrophysiological recording techniques were used in isolated rat spinal cord slice preparations prepared from Chung spinal nerve ligation models of neuropathic pain. Whole-cell recordings from 541 neurones in lamina I/II of the dorsal horn were included in this study. Neurones were first classified based upon differential expression of four subthreshold active conductances, and their passive membrane properties (resting membrane potential, membrane time constant and input resistance). The four active conductances were: a low threshold voltage-dependent calcium conductance (IT); a transient outward potassium conductance (IA); a hyperpolarisation-activated non-selective cation conductance (IH) and an inwardly rectifying potassium conductance (IKIR). Fifteen electrophysiologically distinct cell types were identified. Action potential firing properties were introduced to analyses with cells defined as discharging action potentials transiently (adapting) or continuously throughout a stimulus (non-adapting). With these 21 neuronal subtypes were defined. A further conductance was characterised, described in lamina I/II dorsal horn neurones for the first time: a persistent depolarisation and excitation associated with action potential firing that followed a brief excitatory stimulus delivered by intracellular current injection or activation of dorsal root afferent inputs. These conductances persisted for tens of seconds to minutes following cessation of the activating stimulus and were termed afterdepolarisation potentials (ADPs). Several conductances contributed to ADPs including IH and IT. In summary, here electrophysiological properties of key neurones in the neuropathic spinal cord have been identified that may contribute to the aberrant hyper-excitability of spinal circuits in neuropathic pain. Understanding these mechanisms could lead to new therapeutic strategies to treat this condition.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history Q Science > QP Physiology R Medicine > RC Internal medicine |
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Library of Congress Subject Headings (LCSH): | Chronic pain, Neural transmission, Electrophysiology, Neural conduction, Neuroplasticity | ||||
Official Date: | June 2022 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Spanswick, David C. | ||||
Sponsors: | Neurosolutions Ltd. | ||||
Format of File: | |||||
Extent: | 276 pages : illustrations (colour), charts (colour) | ||||
Language: | eng |
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